Patients who have been immunologically sensitized by a previous transplant, pregnancy, or blood transfusion may not receive a renal transplant due to our current difficulty preventing rejection in such patients. In addition, patients successfully transplanted have an approximately 20% risk of developing B cell sensitization to their functioning kidney allograft and of alloantibody shortening the life of their kidney. Costimulation blockade, in particular agents targeting CD28 and CD40, may offer significant advantages over conventional immunosuppressive agents in preventing and overcoming an alloantibody response. CD28 has recently been shown to be expressed on long-lived plasma cells in bone marrow and necessary for their survival and continued antibody production. Our rodent model data suggest that costimulation blockade may be able to down regulate the B cell response in a donor-specific manner. In order to move toward clinical application in humans, we propose to test costimulation blockade in combination with other putative agents including Belimumab (anti-BAFF), anti-APRIL and Bortezomib (proteasome inhibitor) that target the sensitized immune repertoire of NHP's. We plan to test the ability of such agents alone and in combination with donor bone marrow infusion in order to achieve donor-specific desensitization in a clinically relevant rhesus monkey renal allograft model. Briefly, the model uses monkeys sensitized by a previously rejected renal allograft, and ultimately we aim to achieve immunologic unresponsiveness to a second kidney transplanted from the same donor. We will use state of the art methods developed by us to measure not only T and B cell sensitization and desensitization, but also will measure the affect of treatment on the protective immune response that must remain intact for avoidance of infection. We will build upon lessons learned from our previous UOI grant that focused on the T and B cell response in monkeys developing de novo antibody after renal transplantation. We have already learned that CD28 blockade with Belatacept effectively prevents alloantibody from developing in a rigorous NHP model. We now propose to use a difficult but yet more clinically relevant NHP model to evaluate strategies to desensitize the host.

Public Health Relevance

; The immunologic tools to measure allospecific B cell, plasma cell, and antibody responses in transplantation are relevant to a host of organ transplant recipients and represent a novel contribution to the field. The need for better approaches to treat alloantibody in transplant patients?awaiting transplantation or after transplantation?is well-recognized and this would constitute an important advance in the field.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI051731-12
Application #
8519227
Study Section
Special Emphasis Panel (ZAI1-MFH-I)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
12
Fiscal Year
2013
Total Cost
$656,508
Indirect Cost
$205,992
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Singh, K; Stempora, L; Harvey, R D et al. (2014) Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer. Am J Transplant 14:2691-703
Sullivan, Jeremy A; Adams, Andrew B; Burlingham, William J (2014) The emerging role of TH17 cells in organ transplantation. Transplantation 97:483-9
Pathiraja, Vimukthi; Matar, Abraham J; Gusha, Ashley et al. (2013) Leukapheresis protocol for nonhuman primates weighing less than 10 kg. J Am Assoc Lab Anim Sci 52:70-7
Huang, Alex Y; Haining, W Nicholas; Barkauskas, Deborah S et al. (2013) Viewing transplantation immunology through today's lens: new models, new imaging, and new insights. Biol Blood Marrow Transplant 19:S44-51
Lowe, M C; Badell, I R; Turner, A P et al. (2013) Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy. Am J Transplant 13:312-9
Page, Eugenia K; Courtney, Cynthia L; Sharma, Prachi et al. (2013) Post-transplant lymphoproliferative disorder associated with immunosuppressive therapy for renal transplantation in rhesus macaques (Macaca mulatta). Exp Toxicol Pathol 65:1019-24
Badell, I R; Russell, M C; Cardona, K et al. (2012) CTLA4Ig prevents alloantibody formation following nonhuman primate islet transplantation using the CD40-specific antibody 3A8. Am J Transplant 12:1918-23
Badell, I R; Thompson, P W; Turner, A P et al. (2012) Nondepleting anti-CD40-based therapy prolongs allograft survival in nonhuman primates. Am J Transplant 12:126-35
Johnson, Z P; Eady, R D; Ahmad, S F et al. (2012) Immunogenetic Management Software: a new tool for visualization and analysis of complex immunogenetic datasets. Immunogenetics 64:329-36
Page, A; Srinivasan, S; Singh, K et al. (2012) CD40 blockade combines with CTLA4Ig and sirolimus to produce mixed chimerism in an MHC-defined rhesus macaque transplant model. Am J Transplant 12:115-25

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