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PRE-TRANSPLANT CONDITIONING AND THE ROLE OF THE
MICROENVIRONMENT DURING HEMATOPOIETIC RECONSTITUTION
by
Jacob Andrade
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR, AND CELLULAR BIOLOGY)
December 2010
Copyright 2010 Jacob Andrade
Object Description
| Title | Pre-transplant conditioning and the role of the microenvironment during hematopoietic reconstitution |
| Author | Andrade, Jacob |
| Author email | jacoband@usc.edu; Andrec60@hotmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Genetic, Molecular & Cellular Biology |
| School | Keck School of Medicine |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-09-13 |
| Advisor (committee chair) | DeClerck, Yves |
| Advisor (committee member) |
Kim, Yong-Mi Lutzko, Carolyn Crooks, Gay M. |
| Abstract | Treatment related mortality due to bone marrow transplantation is primarily caused by immune system dysfunction, leading patients to succumbing to opportunistic infections. Clinicians are faced with the challenge of needing to suppress the patients’ immune system in order to prevent donor cell rejection. Subsequently, suppressing immune function necessitates extensive supportive therapy while donor cells recapitulate the immune system. The delay in immune recovery after marrow engraftment is dependant on the ability of donor hematopoietic progenitors to egress the marrow and reconstitute thymopoiesis in the host thymus. Unfortunately, the ability of the thymus to support thymopoiesis diminishes with age, especially after chemo-/radio- therapy used in the conditioning process. Non-myeloablative conditioning regimens, including low dose irradiation, have been successful in the clinical setting to reduce organ toxicity. However, non-myeloablative conditioning only allows for partial engraftment of donor cells into the host marrow creating a chimeric hematopoietic and immune system. In order to decrease the risk of treatment related mortality to the patient, understanding how to improve donor chimerism after non-myeloablative conditioning will be important to obtain higher engraftment than ablative regimens. It is currently not well understood how non- myeloablative conditioning of the host allows for host cell engraftment in the marrow.; This dissertation begins by examining the effect of sub-lethal irradiation on engraftment of donor bone marrow cells. Based on the data presented in chapter two, I hypothesize that signals from the host marrow after sub-lethal irradiation stimulate proliferation of donor cells. In chapter three of this dissertation, work is presented on the changes in expression of mitogenic and chemotactic factors in the bone marrow of the irradiated host. Although I provide evidence for increases in mRNA of mitogenic factors, a lack of correlation with protein levels limits the physiologic relevance of this observation. Apart from being able to stimulate hematopoiesis, mitogenic factors such as Hepatocyte Growth Factor have also been implicated in thymic and T cell development. Chapter four of this dissertation discusses the role of hepatocyte growth factor in the thymic microenvironment in the context of thymopoiesis and as a potential factor to obtain a faster and better immune recovery. |
| Keyword | bone marrow transplantation; effects of irradiation conditioning; thymic ontogeny |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3437 |
| Contributing entity | University of Southern California |
| Rights | Andrade, Jacob |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Andrade-3921 |
| Archival file | uscthesesreloadpub_Volume32/etd-Andrade-3921.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | PRE-TRANSPLANT CONDITIONING AND THE ROLE OF THE MICROENVIRONMENT DURING HEMATOPOIETIC RECONSTITUTION by Jacob Andrade A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (GENETIC, MOLECULAR, AND CELLULAR BIOLOGY) December 2010 Copyright 2010 Jacob Andrade |
