All ETDs from UAB

Advisory Committee Chair

Frances E Lund

Advisory Committee Members

Paige M Porrett

John F Kearney

Jan Novak

Sean R Stowell

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

HLA-reactive antibodies (HLA-Abs) to mismatched polymorphic HLA molecules are one of the major barriers to successful organ transplantation. However, key knowledge gaps remain surrounding the immunology of the anti-HLA B cell response in transplant rejection. This lack of understanding regarding the phenotype and specificity of the anti- HLA B cell response means that the field cannot develop optimal therapies to treat B-cell mediated donor-specific responses and that it lacks the tools to optimally match donors and recipients to prevent rejection events. Therefore, this dissertation aimed to explore the clinical factors associated with the formation of donor-specific antibodies and the molecular and structural factors that contribute to the immunogenicity of HLA epitopes in organ transplant rejection. In Paper #1, we examined how viral infection was associated with donor-specific HLA-Ab responses, finding that following infection with SARS-CoV- 2, HLA-Ab responses were common, were associated with impaired allograft function, and that therapies which decreased viral replication were associated with protection from alloimmune events. In Paper #2, we studied the molecular and structural basis for B cell epitope targeting in transplant rejection, demonstrating that the alloimmune response relies on highly exposed and topographically accessible mismatched residues to generate a donor-specific response. In addition, we showed that this response required extensive recognition of self – suggesting that traditional tolerance mechanisms may fail in the iv context of allorecognition. Together, these findings provide a framework for understanding the immunogenicity of nonself in organ transplantation as well a lens for understanding self-recognition and breaches of tolerance in autoimmunity.

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