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.
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.
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.
|Last Updated on Wednesday, 09 January 2013 13:45|