| The major clinical problem following hematopoietic cell transplantation remains relapse. For example, 75–85% of stage IV breast cancer patients will ultimately relapse following autologous transplantation. This dissertation is based on the hypothesis that progression of the malignancy before transplant and relapse following transplant is due to T cell deficiency that prevents an effective anti tumor response. Furthermore, T cell recovery following hematopoietic cell transplant is dependent on the presence of blood dendritic cells, and de novo production of naive T cells in the thymus. These hypotheses are addressed by an immune recovery project with the following four goals: to define the extent of T cell deficiency in hematopoietic cell transplant recipients; to relate T cell deficiency to relapse; to characterize biological mechanisms involved in these deficiencies; and, finally, to relate these biological mechanisms to relapse free survival.; Many of the patients were T cell deficient prior to transplant and remained T cell deficient for up to a year post-transplant. Furthermore, T cell levels significantly associated with relapse free survival pre- and post-transplant in the autologous setting, and post-transplant in the allogeneic setting. Specifically, pre-transplant CD4+CD45RA-CD62L-memory T cells demonstrated a clinically significant correlation with relapse free survival in the autologous setting. Additionally, pre-transplant CD4+CD45RA-CD62L-memory T cells exerted their anti-tumor effect independent of the sensitivity of the tumor to chemotherapy; type of disease; stage of disease; other T cell levels; and for breast cancer, Her2/neu status.; Numerous, significant correlations exist between T cell levels and blood dendritic cells pre- and post-transplant. Additionally, significant correlations exist between T cell levels and recent thymic emigrants pre-transplant, but not in the first six-months post-transplant. This suggests a role for blood dendritic cells and thymic production in T cell proliferation. However, only pre-transplant levels of recent thymic emigrants correlated with relapse free survival in the autologous setting, and only for patients with hematologic malignancies. These observations support further investigation into T cell recovery mechanisms, and provide rationale for pre- and post-transplant immunotherapy in the hematopoietic cell transplant setting. |
