Contributing Factors to Immune Cell Repertoire and Effects on Alloreactivity Restricted; Files Only

Espinosa, Jaclyn (2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/b8515p244?locale=en
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Abstract

Memory T cells, and their ability to generate an anamnestic response, are critical to protective immunity, but contribute to allogeneic organ transplant rejection. Allospecific memory can be generated through heterologous cross-reactivity and homeostatic proliferation, as well as through prior allogeneic antigen exposure. Inhibitors of calcineurin and mTOR effectively, but nonspecifically, impede memory T-cell responses. Blocking costimulation, although effective at inhibiting responses to de novo alloantigen, less effectively inhibits allospecific memory responses. CD28:CD80/86 pathway costimulation blockade (CoB) with CTLA4-Ig is known to prevent T cell-mediated allograft rejection in non-allosenstized mice. Clinical use of belatacept, which inhibits the same pathway in humans, provides improved patient and graft survival, improved graft function, and fewer off target side effects compared to calcineurin inhibitors. However, use of CoB in human transplantation has been hampered by the occurrence of CoB resistant rejection (CoBRR), which has been attributed in part to pathogen-driven T cell repertoire maturation and resultant heterologous alloreactive memory. We identified a population of CD57+PD1- CD4 T cells present prior to transplantation that correlated with CoBRR. Contrary to data recognizing CD57 as a marker of senescence on CD8 T cells, we discovered a non-senescent, cytolytic phenotype associated with CD57+ CD4 T cells. To study factors that contribute to the development of these CoB-resistant cells, we developed a mouse model to evaluate the effects of specific viruses on alloreactivity. Prior murine studies demonstrating virus-induced heterologous alloimmunity have been conducted using acute viral pathogens atypically encountered in humans and CoB regimens not used clinically. We therefore developed a model of virus-induced memory differentiation using murine homologues of clinically prevalent persistent and latent viruses in the presence of maintenance CoB regimens like those used clinically. While infected mice developed a significant and sustained increase in effector memory CD4 and CD8 T cells consistent with that seen in humans, infected mice did not develop heterologous alloreactivity, and were not able to reject primarily vascularized heterotopic heart transplants under treatment with CoB. Thus, memory acquisition alone is insufficient to provoke CoBRR, andlatent or persistent viruses may have limited capacity to stimulate a heterologous alloimmune response.

Table of Contents

Table of Contents

Chapter 1. Introduction……………………………………………………………………1

Chapter 2. CD57+ CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection………10

Introduction………………………………………………………………………11 Materials and Methods……………………………………………………………13 Results…………………………………………………………………………….17

High prevalence of CD57+PD1- CD4 T cells in peripheral blood prior to transplant is associated with belatacept-resistant rejection.

CD57+ CD4 T cells are not senescent by traditional indices.

The gene profile of CD57+PD1- CD4 T cells is highly associated with allograft rejection.

CD57+ cells have increased expression of adhesion molecules.

There is an increased density of CD57+ T cells in rejecting kidney allografts.

CD57+ CD4 T cells are CD28- and exhibit cytolytic properties.

CD57+ CD4 T cells are resistant to the immunosuppressive effects of belatacept.

CD57+PD1- CD4 T cells persist in the periphery following transplantation.

Discussion………………………………………………………………………...23 Figures…………………………………………………………………………….27

Chapter 3. Manipulating Mice to Model the Human Condition…………………………..38

Introduction………………………………………………………………………39 Materials and Methods……………………………………………………………42 Results…………………………………………………………………………….44

Murine immune cell profiles change significantly with age

Treatment with PTH does not significantly alter murine immune cell profiles

Infection with latent and persistent viruses permanently alters murine immune cell profiles

Multiple viral infections can lead to CD28 downregulation in mice

Discussion………………………………………………………………………...47 Figures…………………………………………………………………………….49

Chapter 4. T Cell Repertoire Change Induced by Persistent and Latent Viral Infection is Insufficient to Induce Costimulation Blockade Resistant Organ Allograft Rejection in Mice……………………………………………………………………………56

Introduction……………………………………………………………………....57 Materials and Methods……………………………………………………………60 Results…………………………………………………………………………….63

Infection with latent and persistent viruses permanently alters the murine immune cell repertoire.

Latent and persistent viral infection does not augment IFNg production in response to allogeneic antigen.

Latent and persistent viral infections do not impact allograft survival in the setting of costimulation blockade.

The presence of rapamycin during infection does not alter the kinetics of TEM expansion or allograft survival.

Evidence of chronic rejection in mock infected mice and mice that received all three infections.

Discussion………………………………………………………………..……….68 Figures…………………………………………………………………………….70 Chapter 5. Discussion……………………………………………………………………79

The technical success of transplantation has led to challenges with chronic immune suppression

Development of assays to screen patients at risk for belatacept resistant rejection

Targeting allospecific memory by combining costimulation blockade with other immunosuppressive agents

Inherent species differences prove challenging when developing animal models

Individualized immunosuppression should be the goal

References……………………………………………………………………………….88

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