Over the past two decades, the development of new immunosuppressive agents has greatly improved the early post-transplant survival of lung allograft recipients. Nevertheless, long-term survival has not improved significantly, due to chronic rejection, infections, and malignancies-all attributable to chronic immunosuppression. Although many antigen-independent factors are known or hypothesized to modulate the development of chronic rejection, allo-immunity remains the sine qua non of rejection. The induction of transplantation tolerance offers the promise of not only obviating the need for systemic immunosuppression, but also preventing the development of chronic rejection One of the most established and robust methods of inducing transplantation tolerance is the creation of a chimeric state in the recipient. By engrafting donorderived hematopoietic cells in the host, the recipient is rendered tolerant to donor tissue through central mechanisms. The simultaneous, stable engraftment of both donor and recipient hematopoietic elements in a recipient (a state known as 'mixed chimerism') not only permits a state of transplantation tolerance, but also prevents certain deficiencies in the immunologic repertoire that can be seen in fully chimeric recipients. Our central hypothesis is that the induction of mixed chimerism will induce a state of tolerance in lung allograft recipients that will 1) result in long term graft survival), 2) prevent obliterative bronchiolitis, and 3) eliminate the increased risk of infection and malignancy associated with chronic immunosuppression. Our corollary hypothesis, based on emerging rodent data, is that memory T cells pose a major threat to the establishment of mixed chimerism. We will investigate three different mixed chimerism conditioning regimens aimed at 1) recipients of living-donor lung allografts, 2) recipients of cadaveric lung allografts and 3) transplanted recipients already on chronic immunosuppressive therapy. In collaboration with Project by Benichou, we will study the effects of memory T cells on tolerance induction by mixed chimerism. In collaboration with Project by Madsen and the Pathology Core, we will identify and validate biomarkers that will accurately reflect the presence or absence of a durable tolerant state in lung allograft recipients.

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 #
7907694
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
$255,060
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Aoyama, A; Tonsho, M; Ng, C Y et al. (2015) Long-term lung transplantation in nonhuman primates. Am J Transplant 15:1415-20
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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

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