Immune Modulatory Strategies to Prevent Costimulation Blockade Resistant Rejection Público
Habib, Jakob (Spring 2023)
Abstract
Costimulation blockade (CoB) is a promising new transplant immunosuppression strategy offering improved long-term patient and allograft survival without the nephrotoxicity of calcineurin inhibitors. However, increased risks of acute rejection have impeded the widespread adoption of CoB. This dissertation sought to determine how modulating the current CoB regimen in two separate ways could improve transplant survival. By interrupting the type I interferon receptor (IFNAR) signaling during CoB, fully MHC mismatched BALB/c skin grafted onto C57BL/6J mice survived significantly longer than CoB alone. We determined that IFNAR signaling on recipient hematopoietic cells was the primary contributor to rejection during CoB, and that this treatment regimen showed efficacy in a preliminary pilot study in nonhuman primates. In addition, we explored how modifying the costimulation blockade reagent, by using an anti-CD28 domain antibody (dAb), affects skin graft survival and T cell differentiation in the clinically relevant setting of T cell depletion (TCD) and homeostatic reconstitution. By selectively blocking CD28 signaling, CTLA-4 coinhibition can occur, further inhibiting effector T cell responses and enhancing regulatory T cell function. We found that TCD+anti-CD28dAb improved BALB/c to C57BL/6 skin graft survival compared to anti-CD28dAb alone. Furthermore, we observed reduced CD69 expression on CD4+ and CD8+ T cells in mice that received TCD+anti-CD28dAb compared to TCD alone. In the kidney, the frequencies of tissue resident CD69+CD103+CD4+ T cells were reduced in TCD+CD28dAb compared to TCD alone. We also observed an increased frequency of CD8+Foxp3+ T cells in the blood and kidney of mice given TCD+anti-CD28dAb compared to TCD alone. These findings demonstrate that blocking IFNAR signaling or changing the CoB regimen to selectively target CD28 signaling could lead to improvements critical for the widespread implementation of CoB in the clinic.
Table of Contents
Table of Contents
Chapter 1. Introduction pg.1
Costimulation blockade resistant rejection pg.2
Table 1 pg.4
Type I interferon signaling pg.5
Type I interferon production during transplantation pg.6
Impact of type I interferon on cell subsets pg.7
CD8+ T cells pg.7
Regulatory CD4+ T cells pg.8
Dendritic cells pg.8
B cells pg.9
pDCs: inflammatory or tolerogenic pg.9
Type I interferon signaling blockade pg.10
Impact of CTLA-4 deficiency during costimulation blockade pg.11
Conventional T cells pg.11
Regulatory T cells pg.12
Beyond T cells pg.12
Conclusion pg.13
Chapter 2. Type I interferon signaling in costimulation blockade resistant rejection pg.15
Introduction pg.16
Methods pg.17
Results pg.23
Combined IFNAR and costimulation blockade improves skin graft survival and reduces CD8+ T cell and dendritic cell activation pg.23
IFNAR signaling on the recipient is the primary contributor to costimulation blockade-resistant rejection pg.24
IFNAR signaling on hematopoietic cells are the primary contributors to costimulation blockade-resistant rejection pg.25
IFNAR signaling solely on T cells or Myeloid cells does not drive costimulation blockade-resistant rejection pg.26
Depletion or inhibition of pDCs is insufficient to prevent costimulation blockade-resistant rejection pg.29
Combined costimulation and IFNAR blockade provides long-term survival in a life-sustaining nonhuman primate renal allotransplantation model pg.31
Discussion pg.32
Figures pg.35
Chapter 3. Selective CD28 blockade impacts T cell differentiation during homeostatic reconstitution following lymphodepletion pg.46
Introduction pg.47
Materials and Methods pg.50
Results pg.53
Selective CD28 blockade reverses lymphopenia-induced differentiation of memory CD4+ T cells in the spleen and lymph node pg.53
Selective CD28 blockade during T cell lymphodepletion and reconstitution improves skin graft survival and reduces expression of CD4+ T cell activation and senescence markers pg.54
Selective CD28 blockade reduces the frequency of CD4+ and CD8+ TRM in the kidney in the absence of T cell lymphopenia-induced reconstitution pg.55
Selective CD28 blockade reduces the frequency of FoxP3+ CD4+ T cells but increases the frequency of FoxP3+ CD8+ T cells following T cell homeostatic reconstitution pg.57
CD8+ FoxP3+T cells exhibit distinct cell surface expression profiles compared to CD4+FoxP3+ T cells in the blood and kidney pg.57
Discussion pg.59
Figures pg.63
Chapter 4. Discussion pg.71
Comparing the effects of IFN-⍺ and IFN-β on the immune system pg.71
Shifting IFNAR signaling from IFN-⍺ to IFN-β pg.74
Augmentation of pDCs to prevent IFN-⍺ production pg.75
Hypothetical effect of combined therapies pg.76
Conclusion pg.79
Figure pg.80
References pg.82
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