PREVENTION OF LETHAL GRAFT-VERSUS-HOST DISEASE IN MICE BY MONOCLONAL-ANTIBODIES DIRECTED TO T-CELLS OR THEIR SUBSETS .2. DIFFERENTIAL EFFECTIVENESS OF IGG2A AND IGG2B ISOTYPES OF ANTI-CDS AND ANTI-CD4 MOAB

The effects of rat anti-CD3 and anti-CD4 moAb, of the IgG2a as well as of the IgG2b subclass, on the development of lethal graft-versus-host disease (GVHD) in a fully allogeneic mouse strain combination were co mpared in vivo. After treatment with these moAb, mice recovered from a n initial loss of body weight. Moreover, their survival significantly improved, A single dose of 200 mu g moAb resulted in a complete and lo ng-term survival, which was not the case after treatment with anti-CD4 IgG2a moAb. A dose of at least 1 mg anti-CD4 IgG2a was necessary to i nduce a tolerant state. Mice effectively treated were fully repopulate d with donor-type cells. Flow cytometric analysis of the recipient spl een cells demonstrated that the moAb caused depletion, modulation or c oating of T cells or a combination of these. The moAb with the highest depleting capacity appeared to be anti-CD4 IgG2b moAb. Anti-CD3 IgG2a as well as IgG2b treatment resulted in a strong modulation of CD3 sur face proteins, which was found on all days examined. Modulation of CD4 surface antigens did not occur in the case of anti-CD4 IgG2a moAb tre atment. Anti-CD4 IgG2b moAb treatment, on the other hand, not only cau sed some CD4 modulation, but also, quite unexpectedly, a significant m odulation of the CD3 molecule. Coating was only observed after treatme nt with anti-CD4 IgG2a moAb and lasted at least 1 week. In the first w eek after treatment no effect on the extent of coating or duration of coating of CD4(+) T cells was found if the dose of anti-CD4 IgG2a moAb was increased from 200 mu g to 1000 mu g. These data provide further insight into anti-CD3 and anti-CD4 therapy in GHVD, thereby contributi ng to the development of effective therapeutic protocols in GVHD model s.