Mechanisms of induction of renal allograft tolerance in CD45RB-treated mice

Background. Rejection is the most significant problem in the field of trans plantation. The current goal of transplant immunology is to develop better immunotherapeutic protocols that are aimed at specifically suppressing allo reactivity and preserving an otherwise intact immune system. We have previo usly shown that mice will accept renal allografts indefinitely with normal renal function after two injections of a monoclonal antibody to the CD45RB protein. Furthermore, this antibody will reverse acute rejection when thera py is delayed until day 4 and will still induce tolerance. The mechanisms o f this therapeutic benefit are not known. Methods. BALB/C mice were used as recipients of major multiple histocompati bility complex-mismatched kidneys using C57BL/6 as donors. Immunoperoxidase microscopy and Northern blots for cytokine gene expression were used to st udy the renal allografts. Fluorescence-activated cell sorter (FACS) analyse s of peripheral blood lymphocytes were performed. Phosphotyrosine peptide p hosphatase assays were performed on splenic lymphocyte membranes. Results. A CD45RB monoclonal antibody (MB23G2) induced tolerance and partia lly depletes peripheral blood lymphocytes. A therapeutically ineffective CD 45RB monoclonal antibody (MB4B4) merely coated the circulating lymphocytes. Furthermore, MB23G2 stimulated more tyrosine phosphatase activity than MB4 B4 in mouse T-cell membranes. Conclusions. The clearance of peripheral blood lymphocyte populations and s timulation of protein tyrosine phosphatase activity may be important in the mechanism of tolerance induction by CD45RB therapy, which may be clinicall y relevant in the therapy of organ rejection in humans.