Faculty active in this area of research are listed below. For a brief description of their research interests, click on their name in the list. Clicking on the name at the beginning of the brief description links to their detailed personal website.
|R. Pat Bucy, MD, PhD, Department of Pathology|
|James F. George, PhD, Department of Surgery|
|Judith A. Kapp, PhD, Department of Ophthalmology|
|Roslyn Mannon, MD, Depts of Medicine & Surgery|
R. Pat Bucy, MD, PhD I am interested in the regulation of immune responses by T cells, particularly the forms of regulation that develop in vivo in situations with chronic antigen presence. Conventional experimental systems have used model antigens given in discreet inoculations so that the clearance of antigen is the dominant overall control mechanism. In physiological situations such as solid organ transplantation, chronic viral diseases, and organ specific autoimmune diseases, antigen is usually not cleared, but the immune system develops various control mechanisms that limit immune damage. In addition to my role as the Director of the UAB Medical Scientist Training Program (joint MD/PhD training), my lab is engaged in a wide range of projects with a translational focus, that span the gamut of basic mechanistic studies in mice to active design of human clinical trials. Active current projects include use of TCR transgenic mice to study murine heart transplant tolerance, analysis of T cell population dynamics in response to various forms of immunization, studies of viral and cellular dynamics in SHIV infected Rhesus Macaques, and a substantial series of studies focused on therapeutic immunization of HIV infected people and assessment of changes in immune function in these people. In all of these systems, multiple techniques are used including flow cytometry, immunohistochemistry, cell culture techniques, production of novel transgenic mice, real-time RT-PCR,. and in situ hybridization analysis of viral and cellular RNA species.
James F. George, PhD Dr. George’s research focuses on the mechanisms of transplantation tolerance induction and immunologic mechanisms of vascular disease in solid organ transplant patients. He and his colleagues perform clinical studies using patient data as well as basic molecular studies using a mouse heart and kidney transplantation models. They study the role of T cell mediated innate immune responses in the development of intimal proliferative lesions of the type that are typically found in over 30% of heart transplantation patients after the first three years post-transplantation. They use induced mutant mice to study the role of Interferon-g and other cytokines in the initiation and progression of vascular lesions. Other interests include the mechanisms by which extracorporeal photopheresis results in downregulation of anti-donor responses in vivo, both in animal models and clinical heart transplant patients.
Judith A. Kapp, PhD Dr. Kapp's research focuses on identifying mechanisms of inducing and abrogating immunological tolerance. Our long-term goal is to translate our findings into novel therapies for preventing graft rejection and augmenting tumor immunity.
A long-term goal is to use knowledge gained from tumor studies and the induction of tolerance to develop methods to prolong graft survival. We have studied two transplantation models. This first involves transplantation of retinal pigment epithelial (RPE) cells as a treatment for age-related macular degeneration (AMD), which is the leading cause of blindness in people over the age of 65 in this country. This disease ultimately results from the loss of light sensing (photoreceptor) cells. However, the loss of photoreceptor cells is preceded by loss of the underlying RPE. Replacement of dead or damaged cells with healthy retinal cells is a very promising approach to the treatment of this, and other, retinal diseases that we are investigating. Although the eye is an immunologically privileged site, we have shown that retinal pigment epithelial cells transplanted into the subretinal space of allogeneic mice are rejected within 4 weeks, whereas they are not rejected in syngeneic mice or immunodeficient Rag-1 knockout allogeneic mice (Kapp, J.A., J. Wen, H.P.Langston, and B.C. Barron in preparation). Our goal is to develop methods to prevent rejection by inducing tolerance. To this end, we have produced transgenic mice expressing OVA in the retinal cells, which will be transplanted into syngeneic mice that have been adoptively transferred with OVA-specific TCR transgenic T cells to track specific cellular interactions in vivo. Experiments are currently underway to determine whether RPE expressing OVA are rejected by OVA-specific T cells and whether rejection can be abrogated by induction of tolerance to OVA. We have developed a novel method to track antigen-presenting dendritic cells (Sanjay G., A. Oran, C. A. Maris, J. Wajchman, S. Sasaki, J.A. Kapp, and J. Jacob. Nat. Immunol.. 4:907-912, 2003), which will be used to determine which APC in the eye induce tolerance.
The second transplant model is for the treatment of insulin dependent diabetes mellitus (IDDM). Because human islets are scarce, th laboratory has studied porcine islet xenograft rejection in spontaneously diabetic NOD mice. Islet microencapsulation plus treatment with immunomodulatory agents (CTLA4Ig, MR1 and/or GK1.5) have been shown to prolong graft function significantly but not prevent rejection (Safley, S.A., J.A. Kapp, and C.J. Weber. Cell Transplant. 11:695-705, 2002). The group is clarifying the mechanisms responsible for enhanced survival and identifying the causes of xenograft failure in this system. Because continuous immunosuppressive therapy is currently required to overcome the autoimmune and transplantation barriers of islet recipients, we have begun exploring the delivery of a modified insulin gene to autologous cells as an alternative transplantation strategy. The development an insulin expression construct, which is transcriptionally up-regulated by glucose and down-regulated by insulin in hepatocytes, serves as the basis for this approach. The insulin gene will be delivered by viral vectors to test the hypothesis that autologous non-islet cells, engineered to express insulin, can circumvent both the autoimmune and graft rejection problems of islet transplantation thereby reducing the need for immunosuppressive drugs.
Roslyn Mannon, MD Long term kidney graft failure continues to be a difficult problem in spite of potent immunosuppressive strategies with improved acute rejection rates and short term graft survivals. This is due both to death with a functioning allograft and the associated co-morbidities of kidney failure, as well as primary graft failure. The leading cause of late graft dysfunction and failure is due to a pathological entity characterized by allograft fibrosis and tubular atrophy (IF/TA), a disease with both immunological and non-immunological etiologies, and no specific therapies. To this end, we have developed an active research program in kidney and kidney/pancreas transplantation that spans the spectrum of basic science, translational studies, and clinical research.
Our Transplant Clinical Research Center provides the personnel and infrastructure to engage not only in pharmaceutical-based studies, but supports clinical studies in transplantation that are investigator initiated and sponsored by the National Institutes of Health. Our current studies include investigating the clinical etiologies of kidney allograft failure (NIAID), the genomics of early and late allograft injury (NIAID), immune monitoring after depletional induction therapies (Immune Tolerance Network) and major clinical interventional immunosuppression trials (Clinical Trials in Organ Transplantation—CTOT) sponsored by NIAID.
The long term goal of our laboratory is to identify new mechanisms and associated biomarkers in the detection and treatment of IF/TA. Utilizing rodent models of kidney and heart transplantation and models of calcineurin inhibitor toxicity, we study the cellular, molecular, and physiologic events following transplantation. We have used these models as platforms for translation into our human patients following kidney transplantation through a broad series of analytical techniques including genomics and proteomics.