HLA matched bone marrow transplantation (BMT) with reduced intensity conditioning is a cure for several non-malignant hematological disorders that require chronic transfusion, such as sickle cell disease and aplastic anemia. However, there are unusually high BMT rejection rates in these patients. Rejection correlates with the number of pre-BMT transfusions, and it has been hypothesized that pre-immunization to antigens on transfused blood primes BMT rejection. Moreover, the implementation of leukoreduction in many transplantation centers has not decreased the rejection rates for solid or bone marrow grafts. Leukoreduction reduces greatly the number of transfused leukocytes, but does not eliminate them. Therefore, the goal of this thesis is to investigate the effects of red blood cells on immune responses in the context of transplantation.
Using a novel mouse model of RBC transfusion and MHC matched BMT; we showed that transfusion of RBC products induced BMT rejection across minor histocompatibility antigen (mHA) barriers. While leukoreduction decreases the immunogenicity of RBC transfusion, it is insufficient to prevent BMT rejection. To study the immunogenicity of the RBC themselves, we generated a novel transgenic mouse with RBC specific expression of a model mHA: the HOD mouse. Using this model we demonstrated that transfusion of HOD RBCs does not induce rejection of mHA expressing BMT. On the contrary, adoptively transferred CD8+ T cells were activated upon stimulation by HOD RBCs but quickly decreased in number in the spleen, suggesting a deletional tolerance mechanism. Together, these data suggest that mHAs on RBCs themselves are not capable of inducing BMT rejection under the current conditions but nevertheless suggest a potential for involvement in modulating CD8+ T cell response.
Cellular immunization to mHAs is neither monitored nor managed by current transfusion medicine practice; however, the current data suggest that immune responses to mHAs on RBCs may represent an unappreciated and significant consequence of transfusion.
Table of Contents
Chapter 1 - Introduction 1
Transfusion medicine 3
Bone marrow transplantation in non-malignant blood disorders 10
Minor histocompatibility antigens in transplantation 12References 20
Figure Legends 3
Chapter 2 - Minor Histocompatibility Antigens On Transfused Leukoreduced Units of Red Blood Cells Induce Bone Marrow Transplant Rejection in a Mouse Model 36Abstract 37 Introduction 38
Materials and methods 40Results 46 Discussion 54 References 58
Figure Legends 65
Chapter 3 - Cross-Presentation of a Minor Antigen on Transfused Red Blood Cells Leads to Deletion of Alloreactive CD8 T cells 73Abstract 74 Introduction 75
Materials and methods 77Results 81 Discussion 89 References 93
Figure Legends 99
Chapter 4 - Modeling Bone Marrow Transplant Rejection by Minor Histocompatibility Antigen Mismatched Red Blood Cell Units 107Abstract 108 Introduction 109
Materials and methods 111Results 117 Discussion 126 References 132
Figure Legends 135
Chapter 5 - Discussion 146Summary 147 Discussion 149
Future Directions 156
General conclusions 160References 161
About this Dissertation
|Committee Chair / Thesis Advisor|
|Minor Antigens on Transfused Red Blood Cells in Immunity and Tolerance ()||2018-08-28 15:27:20 -0400||