Publication Date

2012-12-13

Availability

Embargoed

Embargo Period

2014-12-13

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2012-09-13

First Committee Member

Robert Levy

Second Committee Member

Krishna Komanduri

Third Committee Member

Zhibin Chen

Fourth Committee Member

Alberto Pugliese

Fifth Committee Member

Claudia Marcela Diaz

Abstract

Blood cancers result in the deaths of over 50,000 patients worldwide annually. While capable of inducing temporary or occasionally complete remissions in patients with favorable cytogenetics, conventional chemotherapy is limited both by its toxicity and lack of specificity, often causing secondary disease years later. For over 50 years, the techniques of transplantation have been developed through the complicated interpretation of biology and countless lives. Today, developments in the field of hematopoietic stem cell transplantation have led to an increasing use of the therapy in patients of all ages. The main deterrent to the use of transplantation today is the divergent numbers of HLA haplotypes that exist in a widely disseminated species such as man. These haplotypes cause an often lethal reaction wherein the graft attacks the immunosuppressed host, termed a graft vs host reaction, which, in time, becomes graft vs host disease (GVHD). While directly damaging organs, GVHD has secondary effects such as the impairment of post-transplant immune function leaving the patient susceptible to infection. The treatment of this complication has been the major focus of clinical transplantation in recent years and control of the pathology offers both an immediate transplant survival advantage as well the opportunity to maximize the benefit of the ‘foreign’ antigen recognition of a novel immune system, which manifests itself as graft vs tumor (GVT or graft vs leukemia, GVL). In this work, we develop, and study, a pre-clinical model of GVHD and apply the use of two clinically relevant therapies for GVHD prophylaxis, post-transplant cyclophosphamide (PTC) and Tregs, the application of which holds promise for improved immune reconstitution in recipients of AHCT.

Keywords

GVHD, Cyclophosphamide, Hematopoietic, Transplantation, Allogeneic

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