While transplantation represents life-saving therapy for many patients with end-stage organ failure, longtermoutcomes of transplant remain inadequate, with high rates of chronic organ rejection and theequirement for life-long therapy with costly immunosuppressive agents that dramatically increase the risksof cardiovascular disease, infections and malignancies. The development of strategies to promote theacceptance of allogeneic tissues without the need for chromic immunosupression could not only reduce therisk of these life-threatening complications, but also greatly expand the application of organ, tissue andcellular transplantation. In rodent models, strategies using CD28 and CD40/154 T cell costimulationblockade in the setting of mixed-chimerism induction have led to robust tolerance to both bone marrow andsolid organ allografts. In this proposal, we will test this combined costimulation blockade/chimerisminductionstrategy in Rhesus macaques in order to rigorously determine the requirements to translate theresults in rodent models to clinical care. The unifying purpose of our proposal is to develop clinicallyapplicable protocols for the induction of tolerance to solid organ allografts while preserving immunecompetence in the transplant recipient. In order to accomplish this goal, a detailed understanding of thedegree of MHC disparity between transplant donors and recipients, the immune consequences of transplant,and the protocols that allow the efficient expansion and analysis of adoptive immunotherapeutics arerequired. This core will be focused on providing these key cross-project evaluations that will be crucial tothe success of both of the projects described in this proposal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI051731-06
Application #
7323819
Study Section
Special Emphasis Panel (ZAI1-PA-I (M1))
Project Start
2007-07-01
Project End
2012-05-31
Budget Start
2007-06-15
Budget End
2008-05-31
Support Year
6
Fiscal Year
2007
Total Cost
$217,656
Indirect Cost
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Taraseviciute, Agne; Tkachev, Victor; Ponce, Rafael et al. (2018) Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates. Cancer Discov 8:750-763
Ezekian, Brian; Schroder, Paul M; Freischlag, Kyle et al. (2018) Contemporary Strategies and Barriers to Transplantation Tolerance. Transplantation 102:1213-1222
Mathews, David V; Dong, Ying; Higginbotham, Laura B et al. (2018) CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection. J Clin Invest 128:4557-4572
Kean, Leslie S (2018) Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis. Blood 131:2630-2639
Colonna, Lucrezia; Peterson, Christopher W; Schell, John B et al. (2018) Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation. Nat Commun 9:4438
Kean, Leslie S; Turka, Laurence A; Blazar, Bruce R (2017) Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. Immunol Rev 276:192-212
Kwun, Jean; Manook, Miriam; Page, Eugenia et al. (2017) Crosstalk Between T and B Cells in the Germinal Center After Transplantation. Transplantation 101:704-712
Mathews, D V; Wakwe, W C; Kim, S C et al. (2017) Belatacept-Resistant Rejection Is Associated With CD28+ Memory CD8 T Cells. Am J Transplant 17:2285-2299
Manook, M; Kwun, J; Burghuber, C et al. (2017) Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation. Am J Transplant 17:2055-2064

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