? Project 2 (Knechtle, Project Lead) While perioperative immune cell depletion with either polyclonal antibody or alemtuzumab is used in the majority of renal transplants in the U.S., our lab has shown in both humans and non-human primates (NHP) that homeostatic repopulation following depletion is associated with B cell activation, elevated BAFF levels, and de novo donor-specific alloantibody (DSA). We have also shown that Belatacept is capable of suppressing such DSA in NHP following depletion. Recently, we have shown in a presensitized NHP model that blockade of CD28 and CD154 in combination with proteasome inhibition substantially lowers alloantibody levels pre-transplant, disrupting germinal centers and lowering plasma cell numbers. However, depletion of plasma cells by proteasome inhibition alone is also associated with germinal center and Tfh cell activation. Thus, depletion of immune cells leads to both beneficial and deleterious consequences with respect to tolerance. This project seeks to define the elements of immune cell depletion in sensitized hosts that foster tolerance. We believe that lymphocyte and plasma cell depletion and subsequent homeostatic repopulation present both an opportunity to shape the alloreactive immune repertoire to favor tolerance, and a risk to disrupt regulation, ignite viral infection and induce activation of alloreactive clones. We hypothesize that the consequences of immune cell depletion in sensitized hosts create compensatory responses by the immune system that are predictable and need to be therapeutically controlled to promote tolerance. To explore this hypothesis, we propose 3 specific aims: 1) To develop safer and more effective means to lower the amount and number of allospecific antibodies, plasma cells, and memory B cells that prevent allotransplantation using proteasome inhibition together with complementary adjuvant therapies prior to renal transplantation; 2) To reshape the immune repertoire using depletion, donor-specific transfusion, and rapamycin to promote regulation, AICD, and pro-tolerant homeostatic repopulation in the sensitized recipient; and 3) To evaluate the safety and efficacy of Belatacept with and without Rapamycin as components of post-transplant immunosuppressive regimens promoting long-term survival of renal allografts following desensitization therapy as described in SA1 and 2 above.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI131471-01
Application #
9330425
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2017-08-10
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Manook, Miriam; Kwun, Jean; Sacks, Steven et al. (2018) Innate networking: Thrombotic microangiopathy, the activation of coagulation and complement in the sensitized kidney transplant recipient. Transplant Rev (Orlando) 32:119-126
Ezekian, Brian; Schroder, Paul M; Freischlag, Kyle et al. (2018) Contemporary Strategies and Barriers to Transplantation Tolerance. Transplantation 102:1213-1222
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
Kwun, Jean; Burghuber, Christopher; Manook, Miriam et al. (2017) Successful desensitization with proteasome inhibition and costimulation blockade in sensitized nonhuman primates. Blood Adv 1:2115-2119
Kwun, Jean; Burghuber, Christopher; Manook, Miriam et al. (2017) Humoral Compensation after Bortezomib Treatment of Allosensitized Recipients. J Am Soc Nephrol 28:1991-1996