Basic Science Research

Faculty

Jose G. Avila, MD, PhD Linda Cendales, MD Mandy Ford, PhD Shiv Gangappa, DVM, PhD Neal Iwakoshi, PhD Leslie S. Kean, MD, PhD Allan D. Kirk, MD, PhD Kenneth E. Kokko, MD, PhD Christian P. Larsen, MD, D Phil

Aron E. Lukacher, MD, PhD Robert S. Mittler, PhD David Neujahr, MD Kenneth A. Newell, MD, PhD Thomas C. Pearson, MD, D Phil Allan Ramirez, MD Mark R. Rigby, MD, PhD Colin J. Weber, MD, Dm, Sci

Jose G. Avila, MD, PhD

Assistant Professor
Department of Surgery/Division of Transplantation
Scientific Director of the Cell and Tissue Processing Laboratory

Dr. Avila is an Assistant Professor in the Department of Surgery and the Scientific Director of the Emory Transplant Center (ETC) Cell and Tissue Processing Laboratory. Dr. Avila’s research has been focused on improving organ storage and islet isolation techniques in order to increase islet availability and quality for transplantation. Now, with the aid of an interdisciplinary group conformed by surgeons, basic researchers and technologists he is trying to physiologically and genetically characterize neonatal pig islets (NPI’s) for transplantation into human patients suffering from type I Diabetes Mellitus (T1DM). The recent surge in studies examining xenogeneic sources for islet transplantation in both mouse and non-human primate models demonstrate that the transplant community is entering into a new phase in the effort to utilize porcine donors as a source for islet replacement therapy in the treatment of humans with T1DM. The focus must now include research to obtain critical data in non-human primate models needed to make decisions regarding the design of potential clinical trials using xenogeneic islet tissue in humans. One of our goals is to provide genetic characterization of this tissue, in parallel with islet potency and safety studies currently performed at the ETC. This project uses the expertise of the islet isolation laboratory personnel for the development of procedures to obtain, study and improve NPI for transplantation. In addition, it uses the collaboration of surgeons/researchers for transplantation and follow-up of non-human primates treated with this tissue, using tolerogenic and immunomodulatory protocols currently developed at the ETC.

Recent Publications (2006-2007)

Avila JG, Wang Y, Barbaro B, Gangemi A, Qi M, Kuechle J, Doubleday N, Doubleday M, Churchill T, Salehi P, Shapiro J, Philipson LH, Benedetti E, Lakey JR, Oberholzer J. Improved Outcomes in Islet Isolation and Transplantation by the Use of a Novel Hemoglobin-based O 2 Carrier. Am J Transplant. 2006 Dec; 6(12):2861

Salehi P, Hansen MA, Avila JG, Barbaro B, Gangemi A, Romagnoli T, Wang Y, Qi M, Murdock P, Benedetti E, Oberholzer J. Related Articles, Links Abstract Human islet isolation outcomes from pancreata preserved with Histidine-Tryptophan Ketoglutarate versus University of Wisconsin solution. Transplantation. 2006 Oct 15;82(7):983-5.

Gimi B, Leoni L, Oberholzer J, Braun M, Avila J, Wang Y, Desai T, Philipson LH, Magin RL, Roman BB. Functional MR microimaging of pancreatic beta-cell activation. Cell Transplant. 2006;15(2):195-203.

Linda Cendales, MD

Assistant Professor
Department of Surgery
Emory University School of Medicine and the Atlanta Veteran Affairs Medical Center

Early in her career, Dr. Cendales recognized that applying transplant biology to complex composite tissues requiring innervation, integument barrier function, and motor function would involve as of yet un-defined complexities of immunology, reconstructive surgery, orthopedics and surgical technical science that was not represented in modern medicine, that being, composite tissue allotransplantation (CTA).

The field of CTA comprises the vascularized transplantation of multiple tissues such as skin, muscle, bone, nerve, and tendon as a functional unit, such as a limb. It is envisioned as a means of replacing non-reconstructable tissue defects, such as those created by traumatic amputations or congenital limb malformations. Dr. Cendales' work facilitates the development of this emerging medical field. Her team developed a non-human primate model to test new anti-rejection therapy and has initiated trials to characterize the biology of CTA rejection. These studies in CTA in non-human primates are the largest reported in the scientific literature to date. Her group also conceived of and devised the first classification scheme for human CTA rejection and Dr. Cendales presented these findings as the recipient of a Young Investigator Award from the American Society of Transplantation in 2003. In addition, she organized the first public international consensus discussions conference in CTA at the Ninth Banff Conference on Allograft Pathology in Spain in 2007 resulting in the Banff CTA 2007 classification for skin allograft pathology. Dr. Cendales' goals are to advance this burgeoning emerging discipline from the bench to the bedside in a rigorous academic fashion.

Dr. Cendales is a dually trained hand and transplant surgeon. Her team leads the Microsurgery Laboratory and the CTA program at the Emory Transplant Center. She is an Assistant Professor of Surgery at the Emory School of Medicine and the Atlanta Veteran Affairs Medical Center.

Recent Publications (2005-2007)

Cendales L, Xu H, Bacher J, Eckhaus M, Kleiner D, Kirk A. Composite Tissue Allotransplantation: Development of a Pre-clinical Model in Non-human Primates. Transplantation 2005 Nov27;80(10):1447-1454

Cendales L, Kirk AD, Moresi M, Ruiz P, Kleiner D. Composite Tissue Allotransplantation: Classification of Clinical Acute Skin Rejection. Transplantation 2005 Dec27; 80(12):1676-80.

Kirk AD, Mannon RB, Kleiner DE, Swanson SJ, Kampen RL, Cendales LK, Elster EA, Wakefield T, Chamberlain C, Hoffmann SC, Hale DA. Results from a Human Renal Allograft Tolerance Trial Evaluating T-Cell Depletion with Alemtuzumab combined with Deoxyspergualin. Transplantation 80:1051-9, 2005.

Kirk AD, Hale DA, Ford E, Kleiner DE, Kampen RL, Elster EA, Swanson SJ, Cendales L, Cropper T, Hale L, Jordan S, Koussis T, Peretti J, Sloane A, Salaita C, Ring M, Chamberlain C, Mannon RB. Solid Organ Transplantation at the National Institutes of Health: Development of a Research Based Transplantation Practice. in Clinical Transplants 2005. Cecka and Terasaki (Eds), UCLA Tissue Typing Laboratory, Los Angeles, CA. 2006; 131-144.

Cendales L, Kirk AD. Non-human Primates for the Study of Composite Tissue Allotransplantation. Transplantation 2007 Jan27;83(2):241

 

Mandy Ford, PhD

Assistant Professor
Department of Surgery
Emory University School of Medicine

A major challenge in the field of organ and tissue transplantation is inhibiting the vigorous immune response orchestrated by donor-specific CD4 + and CD8 + T cells. These cells become activated after recognizing alloantigens and receiving appropriate costimulatory signals, including those transduced through the CD28/B7 and CD40/CD154 pathways. One promising therapy designed to regulate the immune response to donor tissue involves the use of reagents designed to block the costimulatory molecules required for T cell activation. The goal of my research is to use transgenic systems with defined alloantigens to carefully dissect the factors necessary to induce and maintain the state of costimulation blockade-induced tolerance. Specifically, we are focused on four different parameters, which independently impact the fate and function of donor-specific T cells. First, we are investigating the role of donor-reactive CD4 + and CD8 + T cell precursor frequency as a critical factor affecting the degree of T cell proliferation, acquisition of effector function, and requirement for costimulatory signals during allograft rejection or acceptance. Secondly, as a corollary to this work, we are interested in defining the effect of the degree of antigenic exposure of donor-specific T cells on the efficacy of costimulation blockade as a means to induce transplant tolerance. Third, we are examining the impact of stimulation history (i.e. naïve versus memory T cells) on the susceptibility of donor-reactive T cells to costimulation blockade-induced tolerance. Finally, we are interested in studying the impact of TCR affinity for peptide:MHC ligand in the susceptibility of T cells to CD28 and CD154 blockade. Understanding the relative influence of these four parameters on donor-reactive T cell activation and differentiation has broad implications for the development of strategies to inhibit these responses.

Recent Publications (2006-2007)

Ford ML, Koehn BH, Wagener ME, Jiang W, Gangappa S, Pearson TC, Larsen CP. 2007. Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation. J. Exp. Med. 204 (2): 299-309.

Ford ML, Wagener ME, Gangappa S, Pearson TC, Larsen CP. 2007. Antigenic disparity impacts outcome of agonism but not blockade of costimulatory pathways in experimental transplant models. Am. J Transplant . 7: 1-11.

Ford, ML and Evavold, BD. 2006. Modulation of MOG 37-50-specific CD8 + T cell activation and expansion by CD43. Cellular Immunology. 240:53-61 .

Shiv Gangappa, DVM, PhD

Dr. Gangappa’s work focuses on the investigation of novel immunotherapeutic strategies for transplantation tolerance in non-human primate and murine models; and mechanisms of viral latency and antiviral immunity in costimulation blockade-induced transplantation tolerance.

Most transplant recipients harbor latent infections of several human herpesviruses, which is not surprising given their wide distribution. If the recipient is seronegative for CMV, EBV, HHV-6, or KSHV, the individual is still at risk of infection from donor organs. Infections with any of these herpesviruses can threaten the survival of both the patient and the graft. EBV, KSHV, and HHV-6 have been considered etiologic agents or cofactors for several malignancies. Between 14% and 28% of kidney transplant recipients with a reactivation of KSHV may develop Kaposi’s sarcoma and the disease can be very aggressive in transplant recipients, with a mortality rate of 34% within 3 years of diagnosis. One of the limitations in studying the mechanisms by which herpes viruses affect allograft survival is the lack of a suitable small animal model owing to their species specificity. A murine herpesvirus, gamma-herpesvirus 68 is genetically related to human gamma-herpesviruses and infects laboratory strains of mice, and therefore serves as a good small animal model to study effects of latent infection on transplant tolerance. Dr. Gangappa’s work in this animal model suggests that latent infection in allograft recipients interferes with tolerance induction. The results from this project were featured in the “What’s Hot, What’s New” plenary summary of important new work at the 2007 American Transplant Congress at San Francisco. Ongoing work is aimed at defining mechanisms by which viral and host factors interfere with tolerance induction, and utilize this knowledge to overcome the tolerance resistance barrier and improve strategies for allograft tolerance.

Dr. Gangappa is a member of the American Society of Transplantation (AST) and the American Society of Transplant Surgeons (ASTS), and is a reviewer for the journals Microbes and Infection and American Journal of Transplantation. He was awarded the AST Basic Science Faculty Development award for 2007-2009 at the American Transplant Congress in San Francisco in May, 2007.

Recent Publications (2006-2007)

Kean LS, Adams AB, Strobert E, Hendrix R, Gangappa S, Jones TR, Shirasugi N, Rigby MR, Hamby K, Jiang J, Bello H, Anderson D, Cardona K, Durham MM, Pearson TC, and Larsen C.P. 2007 . Induction of Chimerism in Rhesus Macaques through Stem Cell Transplant and Costimulation Blockade-Based Immunosuppression Am. J Transplant. 7(2): 320-335.

Gangappa S, Larsen CP, Pearson TC. 2007. Alloimmunity: No TOLL exemption. Am J Transplant.
7(1): 3-4.

Szretter KJ, Gangappa S, Lu X, Smith C, Shieh WJ, Zaki SR, Sambhara S, Tumpey TM, Katz JM. 2007. Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice. J. Virol. 81 (6): 2736-2744.

Ford ML, Koehn BH, Wagener ME, Jiang W, Gangappa S, Pearson TC, Larsen CP. 2007. Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation. J. Exp. Med. 204 (2): 299-309.

Ford ML, Wagener ME, Gangappa S, Pearson TC, Larsen CP. 2007. Antigenic disparity impacts outcome of agonism but not blockade of costimulatory pathways in experimental transplant models. Am. J Transplant. 7: 1-11.

Koehn BH, Williams MA, Borom K, Gangappa S, Pearson TC, Ahmed R, Larsen CP. 20007. Fully MHC-Disparate Mixed Hemopoietic Chimeras Show Specific Defects in the Control of Chronic Viral Infections. J. Immunol. 179 (4): 2616-2626

Neal Iwakoshi, PhD

Assistant Professor
Department of Surgery
Emory University School of Medicine

The unfolded protein response (UPR) is a signaling pathway that is activated when unfolded proteins accumulate in the endoplasmic reticulum (ER). Signals emanating from the ER induce a transcriptional program that enables a cell to survive conditions during which protein folding in the ER is compromised. Our lab is interested in the molecular basis of this highly coordinated response that it is essential for the folding, processing, export and degradation of all proteins emanating from the ER during stressed and normal conditions. The UPR exists in all eukaryotes and consists of multiple signaling pathways. Current projects in the lab are focused on the most conserved of these pathways that involves a transmembrane kinase and endoribonuclease called IRE-1 and its transcriptional activator XBP-1. We employ biochemical and genetic tools to study the mechanisms that regulate the UPR within the immune system. To date the most physiologically relevant system to study the UPR has been the highly secretory immunoglobulin secreting plasma cell. Our studies within the plasma cell have led us to explore molecular events in the ER lumen induced by signals that control B cell differentiation. As our understanding of the molecular details of UPR signaling matures, we are beginning to look to look at other immune cells. Most recently, our studies have begun to examine the UPR in dendritic cells and how this signaling pathway may intersect with the development and function of this critical antigen-presenting cell. The long-term goal of our research is to establish conceptual basis that will translate into therapeutic manipulation of these responses in the settings of inflammatory and autoimmune diseases and transplantation rejection.

Leslie S. Kean, MD, PhD

Fellow and McKelvey Scholar
Department of Pediatrics
Division of Hematology/Oncology/
Bone Marrow Transplantation
Emory University School of Medicine
Emory Transplant Center

Transplantation tolerance, defined as long-term allograft acceptance by an immunocompetent recipient in the absence of immunosuppression, remains an elusive goal of clinical transplantation. The Emory Transplant Center has been at the center of research that has focused on understanding mechanisms leading to transplantation tolerance, with the ultimate goal of translating knowledge of these mechanisms to clinical transplantation. Over the past several years, our group and others have developed strategies targeting the CD40 and CD28 T cell costimulation pathways to control allograft rejection in murine models. By providing costimulation blockade in the peri-transplant period, existing donor-reactive T cells receive “signal one” (supplied by donor cells and antigens) in the absence of “signal two” and are preferentially deleted. This leads to robust, long-term tolerance when normal mice are transplanted under the protection of costimulation blockade. However, when more immunologically complex systems are transplanted with these same techniques, true immunologic tolerance is more difficult to achieve. My work is focused on four specific questions, all related to transplantation tolerance, and its acquisition in immunologically complex model systems:

1. In a highly immunologically active model of a non-malignant hematologic disease (sickle cell disease) what are the major barriers to the acquisition of transplantation tolerance?
2. How do natural killer cells impact the acquisition of transplantation tolerance, and can control of natural-killer alloreactivity produce transplantation tolerance in otherwise resistant models?
3. In the non-human primate model, what are the major barriers to the acquisition of transplantation tolerance, and can we combine blockade of the costimulation pathway with adoptive cellular therapies to achieve robust donor specific tolerance?
4. During bone marrow transplantation in a rhesus macaque model, what are the barriers to tolerance that result in graft-versus host disease, and can these underlying immune barriers be overcome by a costimulation-blockade based immunomodulation strategy?  

Recent Publications (2006 – 2007)

Kean LS., Hamby K., Koehn B., Lee E., Coley S., Stempora L., Adams A., Heiss E., Pearson T., Larsen CP. 2006. NK cells mediate costimulation-blockade resistant rejection of allogeneic stem cells during nonmyeloablative transplantation. Am J. Transplant. Feb;6(2):292-304.

Kean L., Gangappa S, Pearson T, and Larsen CP. 2006. Transplant Tolerance in Non-human Primates:  Progress, Current Challenges and Unmet Needs. Am J. Transplant May, 6:884-893.

Kean, LS, Anderson, AR, Oliva VL, Stempora L, Rigby MR, Pearson TC and Larsen CP. 2006. Immune monitoring in non-human primate transplantation. A review of the “Non-human primate transplantation tolerance models: Immune Assays and Analysis Workshop” held in Atlanta, GA, September, 2005. Transplantation Reviews. 20:139-145.

Kean LS, Adams AB, Strobert E, Hendrix R, Gangappa S, Jones TR, Shirasugi N, Rigby MR, Hamby K, Jiang J, Bello H, Anderson D, Cardona K, Durham MM, Pearson TC, and Larsen CP. 2007. Induction of Chimerism in Rhesus Macaques through Stem Cell Transplant and Costimulation Blockade-Based Immunosuppression. Am J. Transplant 7(2):320-35.

Zahorchak AF, Kean LS, Tokita D, Turnquist HR, Abe M, Finke J, Hamby K, Rigby MR, Larsen CP, Thomson AW. 2007. Infusion of Stably-Immature Monocyte-Derived Dendritic Cells Plus CTLA4-Ig Modulates Alloimmune Reactivity in Rhesus Macaques. Transplantation. In press

Linzie K, Trexler A, Pearson TC, Larsen CP, Rigby MR and Kean LS. 2006. NK cells rapidly reject allogeneic bone marrow in the spleen through a Perforin- and Ly49D-dependent, but NKG2D-independent mechanism. Am J. Transplant, In press

Allan D. Kirk, MD, PhD

Professor and Scientific Director, Emory Transplant Center
Georgia Research Alliance Eminent Scholar
McKelvey Scholar

Dr. Kirk's lab is refuting the conventional wisdom that the immune system must be impaired to prevent transplant rejection. When patients undergo an organ transplant procedure, they must take immunosuppressive medications for life to prevent immune rejection of the transplanted organ. These drugs are relatively non-specific and exact significant costs in terms of infectious, malignant and physiological side effects. Thus, transplant patients trade a disease for a condition. Dr. Kirk's work looks at the immune system not as an offensive system void of regulation, but rather an elegant tightly regulated defensive network that provides protective immunity through measured responses to specific threats to homeostasis. It thus must down regulate responses as well as augment them, and is as capable of preventing rejection as it is of causing it. His research had been directed toward understanding the regulatory aspects of immunity and exploiting them to achieve transplant tolerance - a state in which the immune response favors acceptance of an organ rather than rejection.

Dr. Kirk's primary goals lie in the transition of therapies from the laboratory into proof of concept clinical trials. His group uses both rodent and non-human primate models of transplantation to model therapies for initial clinical use. Therapies that show promise pre-clinically are investigated in humans under approved renal transplant protocols. His lab is currently investigating several methods for tolerance induction as well as investigating the fundamental signals of injury that trigger immune system activation.

Recent Publications (2005-2006)

Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, Swanson SJ, Mannon RB, Roederer M, Kirk AD. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant 5:465-74, 2005.

Hoffmann SC, Hale DA, Kleiner DE, Mannon RB, Kampen RL, Jacobson L, Cendales LC, Swanson SJ, Becker BN, Kirk AD. Functionally significant renal allograft rejection is defined by transcriptional criteria. Am J Transplant 5:573-81, 2005.

Preston EH, Xu H, Dhanireddy KK, Pearl, JP, Leopardi FV, Starost MF, Hale DA, Kirk AD. Synergy between IDEC-131 (anti-CD154), sirolimus, and donor-specific transfusion facilitates operational tolerance following renal transplantation in non-human primates. Am J Transplant 5:1032-41, 2005.

Xu H, Dhanireddy KK, Kirk AD. Human monocytes as intermediaries between allogeneic endothelial cells and allospecific T-cells: a role for direct scavenger receptor-mediated endothelial membrane uptake in the initiation of alloimmunity. J Immunol 176: 750–761, 2006.

Xu H, Zhang X, Mannon RB, Kirk AD. Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell bound CD154. J Clin Invest 116: 769-774, 2006.

Kirk AD . Induction Immunosuppression. Transplantation 82: 503-602, 2006.

Kenneth E. Kokko, MD, PhD

Assistant Professor
Renal Division
Emory University School of Medicine

Emory University maintains an active collaborative research group in the area of transplant immunobiology. Dr. Kokko is interested in the immunologic factors that pose a barrier to acceptance of a transplanted organ such as maintenance of immunologic memory to transplanted organs. At a basic science level, Dr. Kokko has explored the regulatory role of an inflammatory cytokine, interleukin-15, on the maintenance of T lymphocyte memory to a transplanted organ. In collaboration with Dr. Chris Larsen, Dr. Kokko is also using the relatively new technique of intravital microscopy as a means of investigating the regulation of trafficking of memory lymphocytes into a rejecting organ.

In his research on the r egulatory role of interleukin-15 in rejection of skin transplants in a murine model of transplantation, he has found:

• Interleukin-15 deficiency can lead to prolonged survival of skin grafts with minor antigen mismatches but not fully allogeneic mismatches.
• Interleukin-15 deficiency leads to an inability of the host animal to maintain immunologic T cell memory.
• Interleukin-15 deficiency appears to cause a defective alloantibody response with loss of allo-specific antibodies.

Recent Publications (2003 – 2004)

Bose, A, Inoue, Y., Kokko, K.E., Lakkis, F.G. Perforin downregulates CD4 and CD8 T cell-mediated immune responses to a transplanted organ. J. Immun 170: 1611-4, 2003

Adams AB, Williams MA, Jones TR, Shirasugi N, Durham MM, Kaech SM, Wherry EJ, Onami T, Lanier JG, Kokko KE, Pearson TC, Ahmed R, Larsen CP. Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest. 111(12):1887-95, 2003.

Christian P. Larsen, MD, D Phil

Director, Emory Transplant Center
Vice Chair for Research – Department of Surgery
Carlos and Marguerite Mason Professor of Surgery
Department of Surgery
Division of Transplantation
Emory University School of Medicine

Dr. Larsen is an expert in transplantation surgery, immunology and immunotherapy. With the aid of significant grant funding, his research with Drs. Pearson, Newell and Kirk works to establish true immune tolerance among transplant recipients. This research strives to free patients from the toxic side effects of daily immunosuppressant medicines and achieve permanent, long-term acceptance of organs. Areas of primary research focus in his laboratory include: (1) understanding the fundamental mechanisms involved in the T cell response to transplant tissues, specifically the role of costimulatory pathways in T cell activation, and (2) the mechanisms involved in immunologic tolerance to self and transplanted tissues. Drs. Larsen and Pearson have a strong track record of bringing research to the patient – their research in co-stimulation blockade has been brought from basic research in the early 1990s through the primate center and into highly successful clinical trials in humans led by Emory to apply these strategies to the development of a clinically relevant means to achieving hemotopoietic chimerism as a route to clinical transplantation tolerance. Among his many appointments, Dr. Larsen is Professor and holder of the Carlosand Marguerite Mason Chair, Director of Emory Transplant Center, Vice Chairman of Research-Surgery, and Director of Mason Transplantation Biology Research Center. In recognition of Dr. Larsen's "outstanding contributions and preeminence in the field of transplantation", he was honored as the recipient of the 2007 Thomas E. Starzl Prize in Surgery and Immunology in March 2007 at the University of Pittsburgh.

Recent Publications (2006 - 2007)

Newell KA, Larsen CP, Kirk AD. "Transplant tolerance: converging on a moving target." Transplantation. 2006 Jan 15;81(1): 1-6.

Emmanouilidis N, Guo Z, Dong Y, Newton-West M, Adams A, Lee E, Wang J, Pearson TC. Larsen CP, Newell KA. "Immunosuppressive and Trafficking Properties of Donor Splenic and Bone Marrow Dendritic Cells." Transplantation Feb. 2006;81: 455-462.

Kemball C, Lee E, Szomolany-Tsuda E, Pearson T, Larsen CP, Lukacher A. "Costimulation Requirements for Antiviral CD8+ T Cells Differ for Acute and Persistent Phases of Polyoma Virus Infection." J Immunol 2006, 176:1814-1824.

Koehn B., Gangappa S., Miller JD, Ahmed R, Larsen CP. "Patients, pathogens and protective immunity: The relevance of virus-induced alloreactivity in transplantation". J. Immunol. 2006, Mar 1l176(5):2691-6.

Cardona K, Korbutt GS, Zvonimir M, Lyon J, Cano J, Jiang W, Bello-Laborn H, Hacquoil B, Strobert E, Gangappa S, Weber J, Pearson T, Rajotte R, Larsen CP. "Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways." Nat. Med. 2006 Mar;12 (3):304-6. Epub 2006 Feb 26.

Larsen CP, Knechtle SJ, Adams A, Pearson T, Kirk AD. "A New look at Blockade of T-cell Costimulation: A Therapeutic Strategy for Long-germ maintenance immunosuppression." Am J Transplant. 2006 May;6 (5):876-83.

Kean LS, Gangappa S, Pearson TC, Larsen CP. "Transplant tolerance in non-human primates: progress, current challenges and unmet needs." Am J Transplant 2006 May;6 (5):884-93.

Han Lee ED, Kemball CC, Wang J, Dong Y, Stapler DC Jr., Hamby KM, Gangappa S, Newell KA, Pearson TC, Lukacher AE, Larsen CP. "A mouse model for polyomavirus-associated nephropathy of kidney transplants. Am J. Transplant." 2006 May'6(5);913-22.

Newell KA, Larsen CP. "Toward Transplantation Tolerance: A Large Step on a Long Road." Am J Transplant. 2006 June 9.

Newell KA, Larsen CP. "Tolerance assays: Measuring the unknown". Transplantation. 2006 June 15;81(11) 1503-9.

Kean L, Hamby K, Koehn B, Lee E, Coley S, Stempora L, Adams A, Heiss E, Pearson T, Larsen C. "NK Cells Mediate Costimulation Blockade-Resistant Rejection of Allogeneic Stem Cells During Nonmyeloablative Transplantation." Am J Transplant. 2006;6 292-304.

Bray RA, Nolen JDL, Larsen CP, Pearson T, Newell K, Kokko K, Guasch A, Tso P, Mendel JB, Gebel, HM. "Transplanting the highly sensitized patient: The Emory algorithm. Am J Transplant." 2006, 6:2307-2315.

Vezys V, Masopust D, Kemball CC, Barber DL, O'Mara LA, Larsen CP, Pearson TC, Ahmed R, Lukacher AE. "Continuous recruitment of naïve T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection." J Exp Med. 2006 Oct 2;203(10):2263-9.

Li JM, Gorechlad J, Larsen CP, Waller EK. "Apoptotic donor leukocytes limit mixed-chimerism induced by CD40-CD154 blockade in allogeneic bone marrow transplantation." Biol Blood Marrow Transplant. W006 Dec;12(12): 1239-49.

Ford M, Koehn B, Wagener M, Jiang W, Gangappa S, Pearson TC, Larsen CP. "Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation." The Journal of Experimental Medicine. In press 2007.

Gangappa S, Larsen CP, Pearson TC. "Alloimmunity: No Toll Exemption." Am J Transplant. 2007, 7:3-4.

Singh N, Chandler PR, Seki Y, Baban B, Takezaki M, Khaler DJ, Munn DH, Larsen CP, Mellor AL, Iwashima M. "Role of CD28 in Fatal Autoimmune Disorder in Scurfy Mice." Blood. 2007 April 26.

Ford M, Wagener ME, Gangappa S, Pearson TC, Larsen CP. "Antigenic Disparity Impacts Outcome of Agonism but not Blockade of Costimulatory Pathways in Experimental Transplant Models." Am J Transplant. 2007 Jun:7(6): 1471-81.

Aron E. Lukacher, MD, PhD

Associate Professor
Pathology and Laboratory Medicine
Division of Anatomic Pathology and Division of Experimental Pathology
Emory University School of Medicine

Dr. Lukacher's laboratory studies the immune response to infection by oncogenic DNA viruses. They use the well-characterized polyoma virus-mouse model. Polyoma virus, a natural mouse DNA virus, is arguably the most potent experimental oncogenic pathogen known. A major focus of the lab's work is to elucidate mechanisms controlling induction, regulation, and maintenance of effective immunosurveillance against virus-induced neoplasia. Because oncogenic viruses persistently infect their hosts, Dr. Lukacher's lab is also interested in understanding the programming of polyoma-specific memory T cell responses in the setting of chronic encounter with viral antigens. These studies have important implications for development of vaccines to persistently infecting viruses. Most humans are persistently infected by polyomaviruses which can have devastating consequences in immunocompromised individuals. In collaboration with Drs. Larsen and Newell (Dept.of Surgery, Emory University), Dr. Lukacher's lab has developed a kidney transplant mouse model to investigate the pathogenesis of polyomavirus-associated nephropathy, a leading cause of kidney transplant failure. The goal of this lab's research is to develop strategies to manipulate the T cell response to polyoma virus to reverse susceptibility to virus-induced tumorigenesis and prevent kidney transplant rejection.

Recent Publications (2005 - 2006)

Kemball, C.C., E.D.H. Lee, E. Szomolanyi-Tsuda, T.C. Pearson, C.P. Larsen, and A.E. Lukacher. 2006. Costimulation requirements for antiviral CD8+ T cells differs for acute and persistent phases of polyoma virus infection. J. Immunol., in press.

Lee, E.D.H., C.C. Kemball, J. Wang, Y. Dong, D.C. Stapler, Jr., K.M. Hamby, K.A. Newell, T.C. Pearson, A.E. Lukacher, and C.P. Larsen. 2006. A mouse model for polyomavirus-associated nephropathy of kidney transplants. Am. J. Transplant., in press.

Kumar, S., M.J. Skeen, Y. Adiri, H. Yoon, V.D. Vezys, A.E. Lukacher, B.D. Evavold, H.K. Ziegler, and J.M. Boss. 2006. A cytokine promoter/yellow fluorescent protein reporter transgene serves as an early activation marker of lymphocyte subsets. Cell. Immunol., in press.

Kemball, C.C., E.D.H. Lee, V.Vezys, T.C. Pearson, C.P. Larsen, and A.E. Lukacher. 2005. Late priming and variability in epitope-specific CD8+ T cell responses during a persistent virus infection. J. Immunol.174:7590-7960.

 

Robert S. Mittler , PhD

Associate Professor
Department of Surgery
Division of Transplantation and Emory Vaccine Center
Emory University School of Medicine

The focus of Dr. Mittler’s individual research program is the study of mouse and human T-cell costimulation pathways that are essential for productive T-cell responses to foreign antigens. In this context, they hope to learn how to artificially regulate immune responses in humans, either to enhance the response in situations of immunodeficiency and tumorigenesis or to selectively diminish the response to organ transplantation or in autoimmune diseases. They have focused upon T-cell activation regulated by the PD-1 receptor, a negative regulator of T cell activation, and the 4-1BB receptor an activator of T cells. PD-1 is a member of the CD28 family but unlike the CD28 T cell costimulatory receptor, its function is to counterbalance immune activation by turning it down. By blocking this signaling pathway, in conjunction with anti-4-1BB immunotherapy Dr. Mittler’s team hopes to enhance the establishment of anti-tumor immunity to refractive, advanced neuroblastoma and Ewing’s sarcoma, two of the most common and fatal childhood cancers. They further believe that this therapeutic strategy will lead to stronger and more durable immune responses to chronic viral infection. The CD137 receptor (AKA 4-1BB) is an activation inducible member of the Tumor Necrosis Factor Receptor Superfamily (TNFR). A key finding has been that in the mouse, CD137 receptors are preferentially used to activate CD8+ T-cells even though both CD4 and CD8 positive T cells express them. Dr. Mittler’s team collaborating with Drs. Chris Larsen and Tom Pearson was also the first to show that administration of monoclonal anti-CD137 antibodies into mice receiving skin or cardiac allografts rejected their grafts much more rapidly than mice injected with a control mAb. In Drs. Newell and Mittler showed that blockade of the CD137 signaling pathway in mouse small intestine allografts led to graft acceptance. Chris Gilson, a PhD candidate in the Larsen/Pearson lab is now working with Dr Mittler’s group to see whether controlled use of CD137 blocking or activating agents (fusion proteins and mAbs) can replicate the findings of Newell and Mittler in skin allograft transplants. Dr. Mittler’s lab were also the first to show that anti-CD137 mAbs proved remarkably effective in completely eradicating established poorly immunogenic tumors in mice. Subsequently Dr. Mittler’s group provided the first long-term comprehensive study that showed that anti-CD137 treatment reversed the course of established SLE and RA in mice and that the treated lupus mice that normally die before one year of age survived for over two years, the normal lifespan of a mouse. Collectively, these studies have led to the U.S. Patent office to award Dr Mittler and his collaborators three U.S. patents for the use of agents that bind to and affect CD137 function. The last of these was awarded in May 2007.  

Recent Publications (2006 - 2007)

Tobias, P., Foell, J., Werner, C., Burdach, S., Mittler, RS, and Hansen, G. (2006). Signaling through CD137 (4-1BB) Controls T helper 2 cell-mediated allergic Inflammation and airway hyperreactivity. J. Clin. Invest. 116:1025.

Uno, T., Takeda, K., Kojima, Y., Yoshizawa, H., Akiba, H., Rolonk, A., Mittler, R.S., Gejyo. F., Okumura, Smyth, M.J., and Yagita, H. (2006) A rational antibody-based therapy of established cancer that combines tumor cell apoptosis and T cell activation. Nat. Med. 12:693.

Wohlfert EA, Gorelik, L., Mittler, R.S., Flavell, RA, Clark, RB. (2006). Cutting Edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo. J. Immunol. 176:1316.

McMillin, D.W., Hewes, B., Gangadharan, B., Archer, D.R., Mittler, R.S., and Spencer, H.T. (2006). Complete regression of large solid tumors, using engineered drug-resistant hematopoietic cells and anti-CD137 immunotherapy. Human Gene Therapy 17:798

Menoret A, Myers LM, Lee SJ, Mittler RS, Rossi RJ and Vella AT (2006). TGFbeta Protein Processing and Activity through TCR Triggering of Primary CD8+ T Regulatory Cells. J. Immunol. 177:6091.

Niu, L., Strahotin, S., Hewes, B., Zhang, B., Spencer, T., Archer, D., Dillehay, D., Kwon, B.S., Chen, L., Vella, A.T., and Mittler, R.S. (2007). Cytokine-mediated disruption of lymphocyte trafficking, hematopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137 treated mice. J. Immunol. 178:4194.

Irie J, Wu Y, Kachapati K, Mittler RS, Ridgway WM. (2007). Modulating Protective and Pathogenic CD4+ Subsets via CD137 in Type 1 Diabetes. Diabetes 186-96.

Laughlin EM, Miller JD, James E, Fillos D, Ibegbu CC, Mittler RS, Akondy R, Kwok W, Ahmed R, Nepom G. 2007. Antigen-Specific CD4+ T Cells Recognize Epitopes of Protective Antigen Following AVA Vaccination. Infect Immun. 2007 Feb 5; [Epub ahead of print].

Zhang, B., Maris, C.H., Foell, J., Whitmire, J., Niu, L., Song, J., Kwon, B.S., Vella, A.T., Ahmed, R., Jacob, J., and Mittler, R.S. 2007. CD137 T cell costimulation-induced suppression or enhanced immune function during acute viral infection. J. Clin. Invest. 2007. (In Press).

Moens, L., Jeurissen A., Mittler R.S., Wuyts G., Michiels G., Boon L., Ceuppens J.L., Bossuyt X. 2007. Distinct approaches to investigate the importance of the murine 4-1BB-4-1BBL interaction in the antibody response to Streptococcus pneumoniae. J Leukoc Biol. June 5 [Epub. Ahead of print].

Lee SJ, Rossi RJ, Lee SK, Croft M, Kwon BS, Mittler RS, Vella AT. CD134 Costimulation Couples the CD137 Pathway to Induce Production of Supereffector CD8 T Cells That Become IL-7 Dependent. 2007. J Immunol. 179:2203-14. 

David Neujahr, MD

Assistant Professor of Medicine
Associate Medical Director, Lung Transplant

Dr. Neujahr joined the Transplant Center after finishing a fellowship in Pulmonary diseases at the University of Pennsylvania. Dr. Neujahr is engaged in a longitudinal study of the immune system in patients following lung transplantation. The goals of the research are to identify patients who are at risk of accelerated graft loss through the use of novel immune monitoring strategies. This research takes advantage of the unique opportunity to collect immune cells which have migrated into the lung allograft using fiberoptic bronchoscopy.

Recent Publications (2006)

Neujahr DC, Chen C, Huang X, Markmann JF, Cobbold S, Waldmann H, Sayegh MH, Hancock WW, Turka LA. Accelerated memory cell homeostasis during T cell depletion and approaches to overcome it. J Immunol. 2006 Apr 15;176(8):4632-9.

Kenneth A. Newell , MD, PhD

Director, Living Donor Kidney Program
Associate Professor
Department of Surgery
Division of Kidney and Pancreas Transplantation
Emory University School of Medicine

Basic: Clinical evidence such as inferior graft survival and increased rates of rejection demonstrate that intestinal allografts are uniquely immunogeneic. Our laboratory has shown that this is at least in part due to a strong immune response mediated by CD8+ T cells. Importantly, some biologic therapies that inhibit CD4+ T cell function do not impair CD8+ T cell function to the same degree. We have therefore explored alternative strategies for inhibiting CD8+ T cell function including detailed investigation of several TNF receptor superfamily molecules including CD154, membrane lymphotoxin, 4-1BB, and LIGHT. These experiments suggest potential targets of intervening in the immune response to intestinal allografts but also provide more basic insights into the behavior of CD8+ T cells that may be applicable to other disease processes such as autoimmunity and immunity to viral infections and tumors.

Recently we have expanded our studies to include an examination of tissue specific factors that may contribute to differences in the nature of the immune response to different organs. The intestine posses a unique immunologic microenvironment which includes organized secondary lymphoid tissues, specialized immune cell populations, and unique chemokines and integrins to regulate cell trafficking. Our data demonstrate that the secondary lymphoid organs within the transplanted intestine contribute to the process of intestinal allograft rejection and may contribute to the unique immunogenicity of transplanted intestines.

In collaboration with Drs. Christian Larsen and Aron Lukacher we have undertaken studies designed to understand the immune response to polyoma BK virus (BKV) following transplantation. BKV is a common, usually asymptomatic virus that persists in the renal tubular cells of healthy individuals. Over the last decade BKV has emerged as a major pathogen leading to dysfunction and failure of transplanted kidneys. However, little is understood about the mechanisms responsible for the control of BKV following renal transplantation. Making use of unique microsurgical models in mice and immunologic reagents available through the ETC we have submitted an R01 application to the NIH to further investigate BKV-induced nephropathy and evaluate new therapeutic approaches.

Clinical: Outcomes of transplantation have continued to improve dramatically over the last three decades. This is at least in part due to the development of more and better immunosuppressive agents. However, the long-term reliance upon drugs that globally suppress the immune system is associated with numerous deleterious side effects. For this reason, immunosuppressive drug minimization or withdrawal is now an important focus of the transplant community. Two NIH funded projects seek to address this issue. In the first funded project we are studying patients who have maintained excellent graft function despite no longer taking immunosuppressive drugs. This small cohort is recruited from around the world for the purpose of gathering patient data and clinical material to evaluate potential assays predictive of “tolerance”. The results obtained will be compared to several other groups of transplant recipients. A second set of NIH-sponsored trials is intended to develop and validate assays for the purpose of guiding decisions about immunosuppessive drug management. This project is a collaboration among investigators at the Cleveland Clinic, Case Western Reserve, the University of Manitoba, Brigham and Womens’ Hospital (Harvard), the University of California San Francisco, Yale University, and Emory University. It is comprised of a number of sub-studies aimed at developing assays to monitor both the cellular and humoral response to organ allografts and then to use these assays prospectively to manage immunosuppressive medications following kidney, heart, and lung transplantation.

A second major factor contributing to the dysfunction and premature loss of transplanted kidneys is the continued dependence upon nephrotoxic immunosuppressive drugs to prevent rejection. In an investigator-initiated single center study we will examine the potential of efalizumab, an antibody specific for LFA-1 which has been shown to be immunosuppressive and is FDA approved for the treatment of psoriasis, to replace nephrotoxic calcineurin inhibitors following transplantation. This study will also make use of new strategies to monitor the immune response following transplantation that are under development at the ETC.

Recent Publications (2006 – 2007)

Newell, K.A., Larsen, C.P, and Kirk, A.D. Transplantation Tolerance: Converging on a Moving Target. Transplantation 81:1-6, 2006.

Emmanouilidis, N., Guo, Z., Dong, Y., Newton-West, M., Adams, A.B., Han Lee, E.D., Wang, J., Pearson, T.C., Larsen, C.P., and Newell, K.A. Immunosuppressive and Trafficking Properties of Donor Splenic and Bone Marrow Dendritic Cells . Transplantation 81(3):455-462, 2006.

Namasivayan, S., Small, W.C., Kalra, M.K., Torres, W.E., Newell, K.A., and Mittal, P.K. Multi-detector Row CT Angiography for Preoperative Evaluation of Potential Laparoscopic Renal Donors: How Accurate Are We? Clinical Imaging. 30(2):120-126, 2006.

Newell, K.A. and Larsen, C.P. Tolerance Assays: Measuring the Unknown. Transplantation 81(11):1503-1509, 2006.

Han Lee, E.D., Kemball, C.C., Wang, J., Dong, Y., Stapler, D.C., Jr., Hamby, K.M., Newell, K.A., Pearson, T.C., Lukacher, A.E., and Larsen, C.P. A Mouse Model for Polyomavirus-Associated Nephropathy of Kidney Transplants. Am. J. Transplant. 6(5):913-922, 2006.

Green, M., Michaels, M.G., Katz, B.Z., Burroughs, M., Gerber, D., Shneider, B.L., Newell, K., Rowe, D., Hultquist, M., and Reyes, J. CMV-IVIG for Prevention of Epstein Barr Virus Disease and Post Transplant Lymphoproliferative Disease in Pediatric Liver Transplant Recipients. Am J Transplant. 6:1906-1912, 2006.

Newell, K.A. and C.P. Larsen. Toward Transplantation Tolerance: A Large Step on a Long Road. Am. J. Transplant. 6:1989-90, 2006.

Najafian, N. and Newell, K.A. How Can We Measure Immunologic Tolerance in Humans? J. Am. Soc. Neph. 17(10):2652-2663, 2006.

Wang, J., Dong, Y., Sun, J-Z., Taylor, R.T., Guo, C., Alegre, M-L., Williams, I.R., and Newell, K.A. Donor Lymphoid Organs Are a Major Site of Alloreactive T Cell Priming Following Intestinal Transplantation. Am. J. Transplant. 6(11):2563-2571, 2006.

Newell, K.A. and C.P. Larsen. Transplantation Tolerance. Sem. Nephrol. 27:487-497, 2007.

Newell, K.A. and Fryer, J. Immunology of Intestinal Allograft Rejection in Intestinal Failure: Diagnosis, Management, and Transplantation, edited by Langnas, A., Goulet, O., Quigley, E., and Tappenden, K. Blackwell Publishing. To be released Sept 2007 at the International Intestine Transplant Society meeting in Los Angeles, CA.

Thomas C. Pearson , MD, D Phil

Chief, Kidney Transplantation
Livingston Professor of Surgery
Department of Surgery
Division of Transplantation
Emory University School of Medicine

T cells play a central and critical role in the rejection of transplanted organs. Dr. Pearson’s research has focused on better understanding the critical factors for T cell activation and function and the development of novel strategies to block the rejection response. These investigations have involved the development and assessment of novel immunomygelatory strategies in rodent models and pertinent pre-clinical testing in non-human primates. These investigations, on the whole of the costimulatory pathways and the alloimmune response, have the ultimate goal of developing a clinically relevant strategy to induce permanent long-term tolerance to transplanted organs in humans.

Recent Publications (2006 - 2007)

Kean LS, Hamby K, Koehn B, Lee E, Coley S, Stempora L, Adams AB, Heiss E, Pearson TC, Larsen CP. "NK cells mediate costimulation blockade-resistant rejection of allogeneic stem cells during nonmyeloablative transplantation." Am J Transplant 2006 Feb;6(2):292-304.

Kemball CC, Lee ED, Szomolanyi-Tsuda E, Pearson TC, Larsen CP, Lukacher AE. "Costimulation Requirements for Antiviral CD8+ T Cells Differ for Acute and Persistent Phases of Polyoma Virus Infection." J Immunol. 2006 Feb 1; 176(3): 181-24.

Emmanouilidis N, Guo A, Dong Y, Newton-West M, Adams A, Lee E, Wang J, Pearson TC, Larsen CP, Newell KA. "Immunosuppressive and Trafficking Properties of Donor Splenic and Bone Marrow Dendritic Cells." Transplantation 2006;81:455-462.

Cardona K, Korbutt GS, Zvonimir M, Lyon J, Cano J, Joang W, Bello-Laborn H, Hacquoil B, Strobert E, Gangappa S, Weber J, Pearson TC, Rajotte R, Larsen CP. :Long term survival of neonatal porcine islets in honhuman primates by targeting costimulation pathways." Nat. Med. 2006 Mar, 12 (3):304-6. Epub 2006 Feb 26.

Larsen CP, Knechtle SJ, Adams A, Pearson TC, Kirk AD. "A New look at Blockade of T-cell Costimulation: A Therapeutic Strategy for Long-germ maintenance immunosuppression." Am J Transplant. 2006 May;6(5):876-83.

Kean LS, Gangappa S, Pearson TC, Larsen CP. "Transplant tolerance in non-human primates: progress, current challenges and unmet needs." Am J Transplant 2006 May;6(5):884-93

Han Lee ED, Kemball CC, Wang J, Dong Y, Stapler DC Jr., Hamby KM, Gangappa S, Newell KA, Pearson TC, Lukacher AE, Larsen CP. "A mouse model for polyomavirus-associated nephropathy of kidney transplants. Am J. Transplant. 2006 May'6(5);913-22.

Marks WH, Wagner D, Pearson TC, Orlowski JP, Nelson PW, McGowan JJ, Guidinger MK, Burdick J. "Organ donation and utilization, 1995-2004: entering the collaborative era." Am J Transplant. 2006; 6 (5 Pt 2): 1101-10.

Bray RA, Nolen JDL, Larsen C, Pearson T, Newell KA, Kokko K, Guasch A, Tso P, Mendel J, Gebel HM. "Transplanting the highly sensitized patient: The Emory algorithm." Am J Transplant. 2006 6:2307-2315.

Vezys V, Masopust D, Kemball CC, Barber DL, O'mara LA, Larsen CP, Pearson TC, Ahmed R, Lukacher AE. "Continuous recruitment of naïve T cells contributes to heterogeneity of antiviral CD* T cells during persistent infection." J Exp Med. 2006 Sep 11;[Epub ahead of print

Ford M, Koehn B, Wagener M, Jiang W, Gangappa S, Pearson TC, Larsen CP. "Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation." The Journal of Experimental Medicine. In press 2007.

Gangappa,S, Larsen CP, Pearson TC. "Alloimmunity: No Toll Exemption." American Journal of Transplantation. 2007: 7:3-4.

Ford M, Koehn B, Wagener M, Jiang W, Gangappa S, Pearson TC, Larsen, CP. "Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation. The Journal of Experimental Medicine. Vol. 204, No. 2, Feb. 2007:299-309.

Ford M, Wagener M, Gangappa S, Pearson TC, Larsen CP. "Antigenic disparity impacts outcome of agonism but not blockade of costimulatory pathways in experimental transplant models. Am J Transplant. 2007 Jun;7(6):1471-81.

Allan Ramirez, MD

Assistant Professor of Medicine

Dr. Ramirez recently received an NIH KO8 award to study the effects of TGFbeta on the intracellular signaling molecules PPARgamma and Smad3. Using a mouse model of lung transplant, Dr. Ramirez has shown that increased levels of TGFbeta lead to increased Smad3 phosphoralation and subsequent increased in matrix genes responsible for chronic airway remodeling such as seen in bronchiolitis obliterans. Augmentation of PPARgamma using PPARgamma agonists represents a novel way to decrease Smad3 activation and uncouple the link between TGFbeta and chronic rejection.

Recent Publications (2005 – 2006)

Ramirez AM, Shen Z, Ritzenthaler JD, Roman J.Myofibroblast transdifferentiation in obliterative bronchiolitis: tgf-Beta signaling through smad3-dependent and -independent pathways. Am J Transplant. 2006 Sep;6(9):2080-8. Epub 2006 Jun 22.

Force SD, Miller DL, Pelaez A, Ramirez AM, Vega D, Barden B, Lawrence EC.Outcomes of delayed chest closure after bilateral lung transplantation. Ann Thorac Surg. 2006 Jun;81(6):2020-4; discussion 2024-5.

Mark R. Rigby, MD, PhD

Assistant Professor and McKelvey Scholar
Department of Pediatrics
Emory University School of Medicine
Clinical Care Medicine
Children’s Healthcare of Atlanta

As an investigator at the Emory Transplant Center, Dr Rigby primarily studies the immunopathogenisis and prevention of Type 1 diabetes mellitus. Type 1 diabetes mellitus is an autoimmune disease which targets the destruction of the pancreatic beta cells. The Emory Transplant Center is on the forefront of better understanding mechanisms of unwanted immunity, primarily using transplant models. As the cellular mechanisms of transplant rejection and autoimmunity likely have significant overlap, progress in both of these fields helps each other. They directly come together in the study of islet cell transplantation as a cure for T1DM. Islet transplantation is a research focus of Dr. Rigby as well as a clinical investigation focus for Emory Transplant Center. Dr. Rigby’s lab uses animal and cellular models to understand the immunopathogenesis of T1DM such as to identify mechanisms that can be (1) interrupted to prevent disease or (2) modified to allow for immune tolerance induction and therefore allow for immunosuppressive-free islet transplantation. Specifically we are using the NOD mouse model, transgenic diabetogenic T cells, and adoptive transfer systems to identify pathways involved with cellular activation of pathogenic T cells. Other studies are using well-defined reagents to interrupt select T cell activation and survival signals to prevent primary disease or disease recurrence after islet transplantation. In addition, Dr. Rigby is assisting in the Transplant Center in the evaluation of patients receiving islet transplants for Type 1 diabetes and studies in non-human primates optimizing islet transplantation with the goal to make islet transplantation more efficacious and generalizable therapy. With these combined efforts we hope to translate “basic” research on diabetes to clinical benefit.

Recent Publications (2006 – 2007)

Rigby, MR, Alison M. Trexler, AM, Pearson, TC, Larsen, CP. CD28/CD154 blockade prevents autoimmune diabetes by inducing nondeletional tolerance following effector T cell inhibition and regulatory T cell expansion. (Submitted)

Preissig, CM, Hansen, I, Roerig, PL, Rigby, MR. Hyperglycemia is common, can be safely and effectively managed using a protocolized approach, and treatment appears to improve survival in pediatric critical care. (Submitted)

Peddy, S, Rigby, M.R., Shaffner, D.H. Cyanide poisoning in a teenager. Pediatr Crit Care Med. 2006 Jan;7(1):79-82

Rigby, M.R., Biageas, K. Shock: recognition, pathology, and treatment (Book chapter). In: Nichols, D.G., Yaster, M, et al. The Golden Hour. In press.

Colin J. Weber, MD, Dm, Sci

William McGarity Professor of Surgery
Department of Surgery
General and Endocrine Surgery
Emory University School of Medicine

The main focus of Dr. Weber’s research is pancreatic islet transplantation. The long-term goal is to develop techniques for safe and durable islet cell replacement for large numbers of patients with insulin dependent diabetes mellitus. For the past several years, this research has concentrated on the use of xenogeneic tissues as sources of donor islets and microencapsulation plus selective immune modulation of hosts as the means to accomplish cross species islet graft survival. A second focus of research is cause(s) of human parathyroid tumors and their functional characteristics. These studies have concentrated on secreted products of human parathyroid tumors including neuropeptides and cytokines and analyses of replication of parathyroid tumors of differing histopathology.

Researchers Dr. Weber and Dr. Susan Safley are studying transplantation of endocrine cells, such as pancreatic islets and parathyroid cells. Unlike whole organ transplants, cell transplants may be protected from host immune responses by use of microcapsules as immunoisolation barriers. To block islet xenograft rejection, diabetic NOD mice were given CTLA4-Ig (a soluble fusion protein that blocks B7/CD28 interactions) and/or MRI (a mAb that interferes with CD40/CD154 binding). Microencapsulated islets functioned (bg<250 mg/dl) 13 ± 2 days (n=38); MRI treatment (days 0,2,4, and 6) did not prolong survival (11 ± 1days) (n=8). CTLA4-Ig (every other day for 21 days) extended graft survival to 24 ± 3 days (p<0.002, n=29); MRI + CTLA4-Ig further prolonged function to 57 ± 5 days (p<0.001, n=14). In all groups, graft failure was accompanied by a profuse peritoneal cellular infiltrate of macrophages, neutrophils, eosinophils, CD4 + and CD8 + T cells, suggesting that failure was due to rejection. By contrast, chronic treatment with MR1 + CTLA4-Ig extended graft survival to 111 ± 12 days (p<0.002, n=9), over 200 days in some animals. The profile of PEC from these mice was similar to untransplanted control diabetic NODs and was not characteristic of immunologic rejection. Biopsies of 3 mice with functioning grafts (days 130, 144, and 169 post-transplant) revealed intact microcapsules containing healthy islets with no apparent host cellular reaction. These data show that islet microencapsulation plus costimulatory blockade of host immune responses promotes long-term to indefinite survival of porcine islet xenografts.

A second area of research involves studies of secreted products of parathyroid tumors. Parathyroid hormone (PTH) stimulates osteoblasts to produce the proinflammatory cytokine interleukin-6 (IL-6), causing bone resorption. In patients with primary hyperparathyroidism, elevated serum levels of IL-6 normalize after resection of parathyroid tumors. Since IL-6 is also expressed in normal parathyroids and in other endocrine cells (adrenal and islet), we hypothesized that parathyroid tumors might contribute directly to the elevated serum IL-6 levels in patients with hyperparathyroidism. Immunohistochemistry identified IL-6, PTH, and chromogranin-A (an endocrine and neuroendocrine tumor marker) in normal, adenomatous, and hyperplastic parathyroids. By immunofluorescence and confocal microscopy, IL-6 co-localized with PTHand with chromogranin-A in parathyroid cells. All cultured parathyroid tumors secreted IL-6 at levels markedly higher than optimally stimulated peripheral blood mononuclear cells. Supernates from cultured parathyroids stimulated proliferation of an IL-6-dependent cell line, and anti-IL-6 mAb abolished this stimulatory effect. IL-6 mRNA was documented in cultured parathyroid tumors, cultured normal parathyroids, fresh operative parathyroid tumors, and fresh operative normal specimens. In conclusion, these data show that parathyroid tumors and normal parathyroids contain, produce, and secrete IL-6. Our findings present a novel pathway by which human parathyroids may contribute markedly to IL-6 production and elevation of serum IL-6 levels in patients with hyperparathyroidism. The physiologic relevance of IL-6 production by human parathyroids remains to be determined, but IL-6 secretion by parathyroid tumors may contribute to bone loss and to other multi-system complaints observed in these patients.

Recent Publications (2003 – 2004)

Safley SA, Villinger EH, Jackson EH, Tucker-Burden C, Cohen C, Weber CJ. Interleukin-6 production and secretion by human parathyroids. Clin Exp Immunol, January 2004, 145-156.

Safley SA, Kapp LM, Tucker-Burden C, Hering BA, Kapp JA, Weber CJ . Encapsulated porcine islet xenografts in diabetic NOD mice: costimulatory blockade with CTLA4-Ig and anti-CD154 mAb inhibits recruitment of inflammatory cells, induces a shift in peritoneal cytokines, and prolongs xenograft survival. Submitted for publication, May 2004.