Leukemia, aplastic anemia, congenital immunodeficiency, as well as a variety of other hematologic and neoplastic conditions are currently being successfully treated by bone marrow transplantation (BMT). The BMT-procedure is, however, associated with significant morbidity and mortality due to severe alterations of host cellular and humoral immune functions. Some of these BMT-related immunologic deficits, such as in secretory immunity and contact hypersensitivity responsiveness, may last for years following successfully hematopoietic reconstitution. The current research effort to understand depressions in post- BMT immunity has focused primarily on the consequences of graft-versus-host disease. Due to this concentrated effort, significant progress has been made in the prevention and suppression of this once-feared consequence of transplantation. Even in the absence of graft-versus-host disease, it has been noted that the timecourse of immunologic reconstitution within human twin and autologous BMT-recipients is remarkably similar to that observed in allogeneic BMT. We have therefore proposed the hypothesis that endothelial cell toxicity of the preparative regimen contributes to the observed long-term immunologic deficits. Microvascular endothelial cells are known to represent a critical interface between circulating cells of the immune system and the tissues which they must protect. A number of specific lymphocyte surface molecules exist that allow organ-specific adhesion to the microvascular endothelium and subsequent extravasation of these cells. Our studies have identified gamma- irradiation-induced microvascular lesions within the peripheral lymph nodes of mice, which result in a decreased capacity for lymphocyte localization into these organs. Since lymph nodes are a major site of antigen-specific lymphocyte stimulation, as well as amplification and regulation of immunologic responses, alterations in lymphocyte localization to these organs may have significant functional consequences. Our proposed investigations compare three clinically used BMT- preparative agents (gamma-irradiation, busulfan, and etoposide) to establish their relative toxicity to the lymphocyte recirculation process and the eventual immunologic reconstitution of transplanted mice. One of the aims is to analyze changes in the anatomy and function of the lymphocyte receptive regions of the microvascular endothelium following exposure of mice to a given preparative protocol. The overall goal of these studies will be to determine: a) the bone marrow ablative agents least toxic to the lymphocyte localization process, and b) the relationship between lymphocyte recirculation and immunologic recovery of the host following BMT. These studies should have clinical relevance in guiding clinicians as to which BMT preparative regimen might allow the most rapid or complete immunologic recovery following human BMT.
