Immunomodulation in Transplantation:Promoting Tolerance and Protective Immunity Public

Ferrer, Ivana (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/76537221z?locale=fr
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Abstract


Transplantation recipients encounter two significant problems with a
lifetime regimen of immunosuppression. The first issue is that the standard of care
includes the use of such reagents as calcineurin inhibitors that lead to hypertension,
dyslipidemia, type II diabetes, along with significant nephrotoxic side effects,
leading to kidney failure after prolonged treatment. The second is that the same
immunosuppression regimens may lead to recurrent infections of typically
controlled infectious agents in healthy individuals.
Therefore, we interrogated ways to prevent allograft rejection while avoiding
systemic immunosuppression. In Chapters 2-4, we investigated the effects of
transient treatment with anti-CD154 costimulation blockade on innate immune cell
recruitment and donor-specific CD4+ and CD8+ T cell activation and differentiation.
Costimulation blockade significantly protects the graft from cellular infiltration,
which is associated with injury to the structural matrix and cellular structure,
leading to accelerate rejection. Furthermore, anti-CD154 leads to a delayed
differentiation of T cells and promotes T cell conversion into a regulatory
phenotype. In Chapters 5-6, we investigated the effects of mTOR inhibition with
rapamycin on CD8+ T cell differentiation in response to a pathogen or to an allograft.
In these studies, we determined that rapamycin differentially affects T cell
differentiation depending on the context of T cell activation. Treatment with
rapamycin significantly augments pathogen-specific T cell responses while graftâ€
reactive T cell responses are either maintained or diminished with this treatment.
These two studies demonstrate the potential for future treatments in
transplantation. By blocking costimulatory signals, we know we can specifically
target graft-reactive and damaging responses while inducing a regulatory
population to maintain a quiescent state. Furthermore, the transient treatment with
rapamycin shows us that certain therapies can be used to stimulate protective
immune responses against pathogens, while still protecting the transplant from
rejection. Although both of these treatments have their drawbacks, the following
studies demonstrate that both protection of the graft and protection against
infections are achievable goals post-transplantation.

Table of Contents


Table of Contents

Chapter 1: Introduction

Brief History of Transplantation .......................................................................................... 2
Innate Immune Surveillance and Leukocyte Migration ............................................. 4
Activation of T Cell Responses .............................................................................................. 7
Preventing Rejection with Systemic Immunosuppression.....................................10
Preventing Rejection with Costimulation Blockade ..................................................12
Peripheral Tolerance: Regulatory T cells .......................................................................14
mTOR Complex Signal Inhibition with Rapamycin....................................................17
References....................................................................................................................................20

Chapter 2: CD154 Blockade Alters Innate Immune Cell Recruitment and
Programs Alloreactive CD8+ T Cells Into KLRG-1high Short-Lived Effector T Cells

Abstract.........................................................................................................................................41
Introduction ................................................................................................................................42
Materials and Methods ...........................................................................................................46
Results ...........................................................................................................................................49
Discussion ....................................................................................................................................57
Figures and Figure Legends .................................................................................................62
References....................................................................................................................................74

Chapter 3: Antigen--Specific Induced Foxp3+ Regulatory T Cells Are Generated
Following CD40/CD154 Blockade

Abstract.........................................................................................................................................81
Introduction ................................................................................................................................82
Materials and Methods ...........................................................................................................84
Results ...........................................................................................................................................88
Discussion ....................................................................................................................................94
Figures and Figure Legends .................................................................................................99
References................................................................................................................................. 111

Chapter 4: CD40/CD154 Blockade Inhibits Dendritic Cell Production of IL-6
and Alters Balance of Graft-Specific IL-17-Secreting T Cells and Foxp3+ iTreg

Abstract...................................................................................................................................... 120
Introduction ............................................................................................................................. 121
Materials and Methods ........................................................................................................ 125
Results ........................................................................................................................................ 130
Discussion ................................................................................................................................. 137
Figures and Figure Legends .............................................................................................. 141
References................................................................................................................................. 161


Chapter 5: Cutting Edge: Rapamycin Augments Pathogen-Specific but Not
Graft-Reactive CD8+ T Cell Responses

Abstract...................................................................................................................................... 170
Introduction ............................................................................................................................. 171
Materials and Methods ........................................................................................................ 174
Results ........................................................................................................................................ 176
Discussion ................................................................................................................................. 181
Figures and Figure Legends .............................................................................................. 184
References................................................................................................................................. 190

Chapter 6-Unpublished Results: Rapamycin Augments CD8+ T Cell Responses
to Latent and Chronic Infections but Not Heterologous Immune Graft-Reactive
Responses

Abstract...................................................................................................................................... 194
Introduction ............................................................................................................................. 195
Materials and Methods ........................................................................................................ 197
Results ........................................................................................................................................ 201
Discussion ................................................................................................................................. 210
Figures and Figure Legends .............................................................................................. 213
References................................................................................................................................. 223

Chapter 7: Discussion
Targeted Immunosuppression: CD40/CD154 Pathway Blockade ................... 228
To Target CD40 or CD154? That is the Question ..................................................... 236
Assessing Important Interactions Inhibited by CD154-Blockade .................... 243
Paradoxical Aspects of Rapamycin in Transplantation......................................... 247
Concluding Remarks............................................................................................................. 256
Figures and Figure Legends .............................................................................................. 257
References................................................................................................................................. 266


List of Figures and Tables


Chapter 2: CD154 Blockade Alters Innate Immune Cell Recruitment and
Programs Alloreactive CD8+ T Cells Into KLRG-1high Short-Lived Effector T Cells

Figure 2.1......................................................................................................................................62
Figure 2.2......................................................................................................................................64
Figure 2.3......................................................................................................................................66
Figure 2.4......................................................................................................................................68
Figure 2.5......................................................................................................................................70
Figure 2.6......................................................................................................................................72

Chapter 3: Antigen-Specific Induced Foxp3+ Regulatory T Cells Are Generated
Following CD40/CD154 Blockade

Figure 3.1......................................................................................................................................99
Figure 3.2................................................................................................................................... 101
Figure 3.3................................................................................................................................... 103
Figure 3.4................................................................................................................................... 105
Figure 3.5................................................................................................................................... 107
Supplemental Figure 3.1..................................................................................................... 109

Chapter 4: CD40/CD154 Blockade Inhibits Dendritic Cell Production of IL-6
and Alters Balance of Graft-Specific IL-17-Secreting T cells and Foxp3+ iTreg

Figure 4.1................................................................................................................................... 141
Figure 4.2................................................................................................................................... 143
Figure 4.3................................................................................................................................... 145
Figure 4.4................................................................................................................................... 147
Figure 4.5................................................................................................................................... 149
Figure 4.6................................................................................................................................... 151
Supplemental Figure 4.1..................................................................................................... 153
Supplemental Figure 4.2..................................................................................................... 155
Supplemental Figure 4.3..................................................................................................... 157
Supplemental Figure 4.4..................................................................................................... 159

Chapter 5: Cutting Edge: Rapamycin Augments Pathogen-Specific but Not
Graft-Reactive CD8+ T Cell Responses

Figure 5.1................................................................................................................................... 184
Figure 5.2................................................................................................................................... 186
Figure 5.3................................................................................................................................... 188


Chapter 6-Unpublished Results: Rapamycin Augments CD8+ T cell Responses
to Latent and Chronic Infections but Not Heterologous Immune Graft-Reactive
Responses

Figure 6.1................................................................................................................................... 213
Figure 6.2................................................................................................................................... 215
Figure 6.3................................................................................................................................... 217
Figure 6.4................................................................................................................................... 219
Figure 6.5................................................................................................................................... 221

Chapter 7: Discussion

Figure 7.1................................................................................................................................... 257
Figure 7.2................................................................................................................................... 259
Figure 7.3................................................................................................................................... 261
Figure 7.4................................................................................................................................... 263
Table 7.1..................................................................................................................................... 265

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