Immunomodulation in Transplantation:Promoting Tolerance and Protective Immunity Público
Ferrer, Ivana (2011)
Published
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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