Our current mixed chimerism has reliably achieved long-term kidney graft survival exclusively in monkeys (60%) displaying low memory T cell reactivity against their donors prior to transplantation in cynomolgus monkeys (5-7). The presence of regulatory T cells (Tregs) capable of suppressing anti-donor inflammatory responses in vitro was consistently detected in tolerant animals. On the other hand, monkeys displaying high anti-donor memory responsiveness rejected kidney allografts in an acute fashion (6,7). Finally, it is important to note that approximately half of the long-term surviving kidney allografts succumb eventually to chronic rejection (8). These observations stress the need to improve our protocol in order to achieve tolerance to kidney and islet/kidney transplants in 100% of monkeys. Projects 1 and 2 of this program project propose a series of novel strategies designed to induce tolerance to kidney and islet/kidney allografts in monkeys. Successful tolerance induction in both of these studies rely on the basic principles that prevention/suppression of pro-inflammatory alloimmunity combined with enhancement of immune regulation will promote tolerogenesis. Project 3 is 1) to investigate the mechanisms by which the in vivo treatments described in Projects 1 and 2 influence the immune response in monkeys transplanted with allogeneic kidneys, islets or islet/kidneys and, 2) elucidate the nature of the cells, soluble factors and immunological mechanisms involved in induction and maintenance of transplant tolerance. This knowledge will help us determine how to select the appropriate donor/recipient combinations and to refine the treatments proposed in Project 1 and 2 in order to reliably achieve tolerance to kidney and islet transplants in primates. To study this, we propose the following Aims:
Specific aim 1. Investigate donor hematopoietic mixed chimerism, leukocyte recovery and deleterious alloimmune T cell responses in transplanted monkeys Specific aim 2. Investigate regulatory T cell responses associated with transplant tolerance Specific aim 3. Investigate B cell responses and their contribution to rejection and tolerance Understanding the mechanisms by which tolerance is induced and maintained in our primate transplant model should significantly expand the successful application of tolerance protocols in clinical transplantation and for the treatment of immune-mediated diseases requiring tolerogenesis of harmful memory T cells in patients such as autoimmune disorders and allergies.

Public Health Relevance

Project 3 will elucidate the nature of the cells, soluble factors and immunological mechanisms involved in induction and maintenance of tolerance (indefinite survival of transplants without immunosuppression) to kidney and pancreatic islets in non-human primates. Understanding the mechanisms by which tolerance is induced and maintained in our primate transplant model should significantly expand the successful application of tolerance protocols in clinical transplantation and for the treatment of immune-mediated diseases requiring tolerogenesis of harmful memory T cells in patients such as autoimmune disorders and allergies.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI102405-03
Application #
8727743
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Peraino, Jaclyn Stromp; Zhang, Huiping; Rajasekera, Priyani V et al. (2014) Diphtheria toxin-based bivalent human IL-2 fusion toxin with improved efficacy for targeting human CD25(+) cells. J Immunol Methods 405:57-66
Yamada, Y; Ochiai, T; Boskovic, S et al. (2014) Use of CTLA4Ig for induction of mixed chimerism and renal allograft tolerance in nonhuman primates. Am J Transplant 14:2704-12
Scalea, Joseph R; Villani, Vincenzo; Gillon, Bradford C et al. (2014) Development of antidonor antibody directed toward non-major histocompatibility complex antigens in tolerant animals. Transplantation 98:514-9
Scalea, Joseph R; Torabi, Radbeh; Tena, Aseda et al. (2014) The rejuvenating effects of leuprolide acetate on the aged baboon's thymus. Transpl Immunol 31:134-9
Kawai, Tatsuo; Sachs, David H; Sykes, Megan et al. (2013) HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 368:1850-2
Kawai, Tatsuo; Sachs, David H (2013) Tolerance induction: hematopoietic chimerism. Curr Opin Organ Transplant 18:402-7