Major and Minor Alloimmunization Induced Open Access

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

List of Figures

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

About this Dissertation

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology
Keyword	alloimmunization against minor antigens platelet transfusions bone marrow transplantation
Committee Chair / Thesis Advisor	Zimring, James C, Emory University
Committee Members	Lukacher, Aron E, Emory University Evavold, Brian, Emory University Kirk, Allan D, Emory University Altman, John D, Emory University

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