Our recent studies show that, in contrast to laboratory mice, significant numbers of anti-donor alloreactive memory T cells can be detected in cynomolgus monkeys prior to transplantation. These memory T cells are resistant to many conventional immunosuppressive drugs and to costimulation blockade by antibody treatments. It is likely that these cells can rapidly destroy donor cells after bone marrow transplantation thereby preventing the induction/maintenance of chimerism. This is strongly supported by the demonstration that mice that have been adoptively transferred with allospecific memory but not naive T cells can no longer be rendered tolerant to allotransplants via mixed chimerism or costimulation blockade. Based upon these observations, we hypothesize that the presence of allospecific memory T cells in primates prior to transplantation hinders their successful tolerization to allogeneic transplants. To test this hypothesis, we propose two specific aims:
Specific aim 1. Characterize the alloreactive memory T cells present in cynomolgus pre-transplantation Specific aim 2. Evaluate the influence of alloreactive memory T cells on tolerance to and rejection of allogeneic heart and lung transplants. Our preliminary results indicate that, prior to transplantation, the level of alloreactive T cell memory varies dramatically upon the nature of the donor/recipient combination. Here, we will perform heart and lung transplants in donor/recipient combinations with either high or low memory alloreactivity and compare: the alloresponse, the rejection of allografts (acute and chronic), the ability of bone marrow transplant to induce stable mixed chimerism, the tolerogenicty of mixed chimerism and costimulation blockade protocols If successful, this research should significantly expand the successful application of tolerance protocols in heart and lung transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI066705-05
Application #
7907693
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
5
Fiscal Year
2009
Total Cost
$151,009
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Tonsho, M; Lee, S; Aoyama, A et al. (2015) Tolerance of Lung Allografts Achieved in Nonhuman Primates via Mixed Hematopoietic Chimerism. Am J Transplant 15:2231-9
Aoyama, A; Tonsho, M; Ng, C Y et al. (2015) Long-term lung transplantation in nonhuman primates. Am J Transplant 15:1415-20
Yamada, Yohei; Aoyama, Akihiro; Tocco, Georges et al. (2012) Differential effects of denileukin diftitox IL-2 immunotoxin on NK and regulatory T cells in nonhuman primates. J Immunol 188:6063-70
Millington, Timothy; Koulmanda, Maria; Ng, Choo et al. (2012) Effects of an agonist interleukin-2/Fc fusion protein, a mutant antagonist interleukin-15/Fc fusion protein, and sirolimus on cardiac allograft survival in non-human primates. J Heart Lung Transplant 31:427-35
Nadazdin, Ognjenka; Boskovic, Svjetlan; Wee, Siew-Lin et al. (2011) Contributions of direct and indirect alloresponses to chronic rejection of kidney allografts in nonhuman primates. J Immunol 187:4589-97
Nadazdin, Ognjenka; Boskovic, Svjetlan; Murakami, Toru et al. (2011) Host alloreactive memory T cells influence tolerance to kidney allografts in nonhuman primates. Sci Transl Med 3:86ra51
Benichou, Gilles; Yamada, Yohei; Aoyama, Akihiro et al. (2011) Natural killer cells in rejection and tolerance of solid organ allografts. Curr Opin Organ Transplant 16:47-53
Hanidziar, Dusan; Koulmanda, Maria; Strom, Terry B (2010) Creating transplant tolerance by taming adverse intragraft innate immunity. F1000 Biol Rep 2:83
Millington, Timothy M; Madsen, Joren C (2010) Innate immunity and cardiac allograft rejection. Kidney Int Suppl :S18-21
Nadazdin, Ognjenka; Boskovic, Svjetlan; Murakami, Toru et al. (2010) Phenotype, distribution and alloreactive properties of memory T cells from cynomolgus monkeys. Am J Transplant 10:1375-84

Showing the most recent 10 out of 15 publications