IMMUNOLOGICAL AND HEMATOPOIETIC EFFECTS OF CD40 STIMULATION AFTER SYNGENEIC BONE-MARROW TRANSPLANTATION IN MICE

CD40 is a molecule present on multiple cell types including B lymphocy te lineage cells. CD40 has been shown to play an important role in B c ell differentiation and activation in vitro, although little is known concerning the effects of CD40 stimulation in vivo. We therefore exami ned the effects of CD40 stimulation in mice using a syngeneic bone mar row transplantation (BMT) model in an effort to augment B cell recover y after high dose therapy with hematopoietic reconstitution. After the BMT, mice were treated with or without 2-6 mu g of a soluble recombin ant murine CD40 ligand (srmCD40L) given intraperitoneally twice a week . A significant increase in B cell progenitors (B220(+)/ surface IgM(- )) was observed in the bone marrow of mice receiving the srmCD40L. The treated recipients also demonstrated improved B-cell function with in creases in total serum immunoglobulin and increased splenic mitogen re sponsiveness to LPS being noted. Additionally, srmCD40L treatment prom oted secondary lymphoid organ repopulation, accelerating germinal cent er formation in the lymph nodes. Total B cell numbers in the periphery were not significantly affected even with continuous srmCD40L adminis tration. Lymphocytes obtained from mice treated with the ligand also h ad increases in T cell mitogen and anti-CDS mAb responsiveness and acq uired the capability to produce IL-4. Surprisingly, treatment with srm CD40L also produced hematopoietic effects in mice, resulting in an inc rease of BM and splenic hematopoietic progenitor cells in the mice aft er BMT. Treatment with srmCD40L significantly increased granulocyte an d platelet recovery in the peripheral blood. Incubation of BMC with sr mCD40L in vitro also resulted in increased progenitor proliferation, d emonstrating that the hematopoietic effects of the ligand may be direc t. Thus, stimulation of CD40 by its ligand may be beneficial in accele rating both immune and hematopoietic recovery in the setting of bone m arrow transplantation.