Marrow ablative doses of gamma-irradiation and protracted changes in peripheral lymph node microvasculature of murine and human bone marrow transplant recipients.

Gamma-irradiation has been extensively utilized as a bone marrow ablative agent during human bone marrow transplantation. Although the effects of ionizing radiation on lymphoid and hematopoietic cells are well documented, little is currently known about its effect on the nonhematopoietic tissues which are important for the restoration of normal immune function. The vast majority of lymphocyte movement into peripheral lymph nodes takes place via the bloodstream and requires a specific receptor-ligand interaction between the lymphocyte and anatomically distinct postcapillary venules. Due to the importance of lymphocyte recirculation in the initiation and amplification of immune responses, an understanding of the radiosensitivity of the postcapillary venules may provide insight into the pathogenesis of the immune deficiencies commonly seen after bone marrow transplantation. Our studies disclosed that the ability of normal blood-borne lymphocytes to enter peripheral lymph nodes was markedly depressed (less than 50% of normal) in mice which had been exposed to 7.5 Gy of gamma-irradiation. This radiation-induced effect lasted longer than 6 months after irradiation and syngeneic reconstitution, and its magnitude was radiation-dose dependent. Immunochemical staining of the lymph node microvasculature with the monoclonal antibody MECA-325 established that the radiation protocol induced persistent anatomic changes in the lymphocyte-receptive areas of endothelium (high endothelial venules). These vessels developed the appearance of endothelial cell proliferation. Electron microscopy demonstrated significant intracellular edema, with virtual occlusion of many microvascular lumens by edematous endothelial cells. Lymph nodes from human bone marrow transplant recipients were found to exhibit similar ultrastructural changes. These studies for the first time demonstrate that doses of irradiation similar to those used to prepare bone marrow transplant recipients can have significant anatomic and functional sequellae on host endothelial cells.