The approval of belatacept, a 2rd generation CD28 pathway costimulation blocker, represents a new class of immunosuppressive agents. The design, translation and clinical evaluation of belatacept was the culmination of efforts by industry and academia to rationally engineer a new therapeutic. The result is an agent that better preserves renal function, reduces donor-specific antibody formation and mitigates cardiovascular side effects. Despite these significant advances, important challenges remain as belatacept treatment is associated with higher rates and grades of rejection. In addition, current immunosuppressive strategies, including belatacept-based regimens, lack the ability to specifically target donor-reactive responses resulting in a generalized state of immune compromise and infectious susceptibility. Our early studies in mice and non-human primates (NHP) identified costimulation blockade resistant rejection (CoBRR) as an important area for investigation and emphasized the potential benefits of developing a successful tolerance strategy. The recent clinical results with belatacept highlight the pressing need to understand the cellular and molecular pathways that contribute to CoBRR and to develop targeted strategies to overcome them, including clinically applicable tolerance regimens. In the first aim of our project we will evaluate novel 3rd generation costimulation blockade therapeutics in collaboration with our partners in industry including domain antibodies designed to safely and specifically block both the CD28 and CD40 pathways. We anticipate that there will still be a CoBRR response and have new data from preliminary murine and NHP studies suggesting a critical role for the IL-17 pathway. We have also identified a successful strategy utilizing an antibody targeting both IL-12 and IL-23 to control this break-through rejection response.
In aim 2 we will further test this novel IL-12/23 therapy in combination with optimized 3rd generation costimulation blockade. We will synthesize observations from the first two aims to define a successful therapeutic regimen that we will then couple to our novel pulsed donor antigen tolerance strategy. Results from these studies will help develop a clinically translatable tolerance strategy, which avoids the morbidity and mortality of chronic continuous immunosuppression. The new knowledge obtained in these studies will be significant and wilt contribute to improved outcomes, enhanced quality of life, and reduced morbidity by avoiding rejection, simplifying regimens, and avoiding infection as a result of long-term immunosuppression.

Public Health Relevance

Transplantation offers the promise of life saving and health restoring therapy for hundreds of thousands of patients suffering from end-stage organ failure. Outstanding short-term outcomes have been achieved through the development of multi-drug life-long continuous immunosuppressive regimens. Despite these achievements, significant challenges remain that compromise the long-term outcomes and limit the application of transplantation. This grant proposes translational studies to address those challenges.

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 #
8519223
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
$740,162
Indirect Cost
$232,240
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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