Recovery of contact hypersensitivity responses following murine bone marrow transplantation: comparison of gamma-irradiation and busulfan as preparative marrow-ablative agents

Abstract

Bone marrow transplantation (BMT) is often followed by significant morbidity and mortality due to protracted immunodeficiency. We have hypothesized that the bone marrow-ablative regimen may delay the recovery of normal immune function following transplantation by impairing the interaction of host endothelial cells with circulating graft-derived lymphocytes. This report compares the relative effects of busulfan (an alkylating drug) and gamma-irradiation on the tissue-specific localization potential of lymphocytes and the eventual recovery of immune function within syngeneic murine transplant recipients. Localization of normal lymphocytes into peripheral lymph nodes of irradiated BMT recipients was markedly less (less than 50%) than in busulfan-treated or normal mice over the first 2 months post-BMT. This finding correlated with irradiation-induced endothelial cell edema and microvascular occlusions within lymphocyte-receptive areas of the nodal microvasculature. The effect of both preparative regimens on the recovery of contact hypersensitivity (CHS) was also analyzed. This response recovered more quickly (between 1 and 2 months) in busulfan-pretreated animals. Further experiments demonstrated that the decrease in CHS responsiveness appeared, in part, related to a depression in the capacity of lymphocytes to localize into skin sites of antigen deposition within irradiated mice. The impairment of tissue-specific lymphocyte localization may represent a novel mechanism by which whole body irradiation can contribute to delayed immunologic reconstitution following bone marrow transplantation.