Semester

Summer

Date of Graduation

2002

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Laura F. Gibson.

Abstract

The bone marrow microenvironment composed in part of stromal cells provides the niche in which normal hematopoiesis occurs. Hematopoiesis generates cellular components of the immune system and blood through proliferation and differentiation of multipotent hematopoietic stem cells (HSC). In preparation for bone marrow transplantation, radiation or chemotherapy treatment temporarily disrupts the balance of hematopoiesis as many HSC and progenitor cells are destroyed. Following treatment cessation, transplanted HSC and progenitor cells migrate, or "home", back to the bone marrow microenvironment and initiate productive hematopoiesis. While the mechanism of bone marrow homing is not completely understood, several soluble factors and adhesion molecules are known to have specific roles in the process. The chemokine stromal derived factor-1 (SDF-1) and the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) are critical in mediating HSC chemotaxis and adhesion, respectively. In addition, both molecules have been demonstrated to be critical for maintenance of productive hematopoiesis.;We previously demonstrated and characterized stromal cell VCAM-1 protein down-regulation following in vitro exposure to the topoisomerase II inhibitor etoposide (VP-16). VP-16-induced VCAM-1 down-regulation is associated with an impairment of stromal cell layers to support early lymphoid and myeloid cell proliferation. More recently, we evaluated stromal cell SDF-1 protein production following exposure to several chemotherapeutic drugs, and we found that bone marrow stromal cell SDF-1 protein secretion is also disrupted following VP-16 or doxorubicin exposure. SDF-1 protein reductions correlated with a reduced capacity of B-cell progenitor lines to migrate toward chemotherapy-treated stromal cell layers. Finally, we have generated and characterized murine stromal cell lines that constitutively express human VCAM-1 protein. Human VCAM-1 expression is maintained following exposure to VP-16 and overall elevation of VCAM-1 protein offset diminished viabilities in B cell progenitors following removal of exogenous IL-7.;This research will contribute to better understanding mechanistic models that address the hypothesis that aggressive chemotherapy disrupts immune system reconstitution through bone marrow microenvironment damage and disruption of molecules that regulate homing. Ultimately, this work may improve our understanding of delayed immune system recovery following aggressive chemotherapy and lead to enhanced cancer treatment strategies.

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