Major and Minor Alloimmunization Induced Open Access
Patel, Seema Rajnikant (2011)
Abstract
Major and Minor Alloimmunization Induced by Platelet
Transfusions:
Mechanisms, Consequences, and Interventions
By
Seema Rajnikant Patel
In response to vasculature injury, anucleated cell fragments,
referred to as platelets,
adhere and aggregate to damaged blood vessels to preserve
hemostasis through clot
formation and wound healing. Platelet disorders resulting in low
platelet counts or
dysfunctional platelets can require aggressive platelet transfusion
support to aid in
maintaining proper hemostasis levels. Although a vital therapy,
platelet transfusions are
associated with long-term clinical consequences, such as
development of donor specific
alloimmunity and consequential refractoriness to subsequent
platelet transfusions.
When successful, bone marrow transplantations are a potential cure
for the above
patients. In a non-malignant setting, eligible patients can receive
Human Leukocyte
Antigen (HLA)-matched bone marrow transplant. Due to the absence of
neoplasia in
such patients, it is difficult to justify the toxic effects of
stringent conditioning regimens
that are otherwise beneficial in eradicating cancerous cells and
promoting engraftment.
Thus, many physicians choose to transplant under reduced intensity
conditions.
However, under these conditions, it is observed that chronically
transfused patients
reject the HLA-matched bone marrow transplant at higher rates than
minimally or un-
transfused patients. Because the transplants are HLA-matched or
-identical, it is
predicted that rejection is due to minor histocompatibility
antigens. Therefore, the goal
of the current dissertation is to test and characterize the role of
prior alloimmunization
against minor histocompatibility antigens, expressed by transfused
platelet units, in the
rejection of an MHC-identical, unrelated donor bone marrow
transplant. The data
presented herein demonstrate that minor histocompatibility
antigen reactive cellular
alloimmunity induced in response to allogeneic leukocyte reduced
platelet transfusions
can induce rejection of a subsequent MHC-matched bone marrow
transplant expressing
the target minor histocompatibility antigens under reduced
intensity conditions. To the
extent that the observed murine biology reflects human physiology,
these findings
additionally indicate potential clinical interventions to overcome
refractoriness to platelet
or red blood cell transfusions and rejection of an HLA-matched
transplant under
reduced intensity conditions in allogeneic platelet transfused
patients.
Table of Contents
Table of Contents
Chapter 1 - Introduction
…………………….………..………..……………..…
1
Transfusion
Medicine…...………………….…………………...........…...
5
Bone Marrow Transplantations in non-malignant
hematologies.....….. 25
Role of Minor Histocompatibility Antigens in
Transplantation.….......... 30
CTLA4-Ig co-stimulation blockade therapy in
transplantation...……....
43
References………………………………………………………..…..........
50
Chapter 2 - Transfusion of Minor Histocompatibility
Antigen-Mismatched
Platelets Induces Rejection of Bone Marrow Transplants in
Mice…....... 68
Abstract………………………………………………………….................
69
Introduction……………….………………………………………………...
70
Materials and
Methods……..…………………………………………......
72
Results…………………....…………………………………………….......
77
Discussion…………………………………………………………………..
84
References………………………………………………………………….
89
Figure
Legends………………………………………………………...…..
95
Figures and
Tables…………………………………………………….…..
98
Chapter 3 - Mechanisms of Alloimmunization and Subsequent BMT
Rejection
Induced by Platelet Transfusion in a Murine
Model…..………………..…
103
Abstract………………........……………………………………………....
104
Introduction………………………………………………………...………
105
Materials and
Methods……………………………………………………
107
Results…………………………………………………...…………….......
114
Discussion………………………………………………………………….
123
References…………………………………………………………………
127
Figure
Legends………………………………………………………...….
131
Figures and
Tables………………………………………………………..
135
Chapter 4 - Alloimmunization against RBC or PLT Antigens is
Independent of
TRIM21 Expression in a Murine
Model………………………………...…….
140
Abstract…………………………………………………………………….
141
Introduction……………………………………………...…………………
142
Materials and
Methods……………………………………………………
145
Results……………………………………………………………...….......
148
Discussion………………………………………………………………….
151
Conclusions………………………………………………………………..
153
References…………………………………………………………...........
154
Figure
Legends…………………………………………………...……….
157
Figures and
Tables……………………………………………................
159
Chapter 5 - Co-stimulatory Blockade Prevents Rejection of
MHC-matched Bone
Marrow Transplants in Platelet Transfused
Mice………………………….162
Abstract………………………………………………………..................
163
Introduction……………………………………...…………………….….
164
Materials and
Methods……………………………………………..……
167
Results……………………………………………………………............
172
Discussion………………………………………………………..……….
179
References……………………………………………………….............
183
Figure
Legends…………………………………….…………….……….
186
Figures and
Tables………………………………………...…................
191
Chapter 6 -
Discussion………………………………………………..………
196
Summary………………………………………………………...………..
197
Discussion……………………………………………………...…………
202
Future
Directions……………………………………………...………….
221
General
Conclusions………………………………………...…………..
229
References…………………………………………………...….………..
230
Figure
Legends……………………………………………...……………
240
Figures and
Tables………………………………………...…………….
242
Chapter 2
Figure
1……………………………………………………………………......
98
Figure
2……………………………………………………………………......
99
Figure
3……………………………………………………………………......
100
Figure
4……………………………………………………………………......
101
Chapter 3
Figure
1……………………………………………………………………......
135
Figure
2……………………………………………………………………......
136
Figure
3……………………………………………………………………......
137
Figure
4……………………………………………………………………......
138
Figure
5……………………………………………………………………......
139
Chapter 4
Figure
1……………………………………………………………………......
159
Figure
2……………………………………………………………………......
160
Figure
3……………………………………………………………………......
161
Chapter 5
Figure
1...………………………………………………………………..........
191
Figure
2...………………………………………………………………..........
192
Figure
3...………………………………………………………………..........
193
Figure
4……………………………………………………………………......
194
Figure
5……………………………………………………………………......
195
Chapter 6
Figure
1………………………………………………………………………..
242
Figure
2………………………………………………………………………..
243
Figure
3………………………………………………………………………..
244
List of Tables
Chapter 2
Table
1..……………………………………………………………...............
102
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