Research
Emory Transplant Center is on the forefront of evaluating approaches and novel immunosuppressive regimens for clinical islet transplantation. Our focus is to use animal and cellular models to understand the immunopathogenesis of this disorder. By understanding these mechanisms they 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 tolerance induction protocols systems previousy identified from Dr. Larsen’s laboratory – like co-stimulatory blockade – to prevent primary disease or disease recurrence after islet transplantation. With other efforts in the Transplant Center – like ongoing large animal models and clinical studies of islet transplantation -- this work can be translated to bring this “basic” research to clinical fruition.
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 PTH and 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.
Clinical Trials
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