SUPPRESSION OF SYNTHESIS OF NATURAL ANTIBODIES BY MYCOPHENOLATE MOFETIL (RS-61443) - ITS POTENTIAL USE IN DISCORDANT XENOGRAFTING

One of the major barriers to successful transplantation of immediately vascularized organs between discordant species is the presence of nat ural antibodies (NA) in the recipient. While natural antibodies can be depleted by plasmapheresis and/or organ absorption, they rapidly retu rn to the circulation after such procedures. It will be desirable to s uppress NA for longer periods of time. Since NA appear to be produced at least in part by CD5+ B cells, it was important to evaluate whether mycophenolate mofetil (RS-61443), a novel immunosuppressant that has been shown to suppress normally elicited antibody synthesis, would als o be able to suppress NA. Adult rats were splenectomized, and 2 days l ater, 9 plasma exchanges, each of 4 ml, were performed. One group of r ats received RS-61443 at 40 mg/kg/day (the dose described as efficacio us for suppressing elicited antibodies in rats) starting immediately a fter the last exchange for 7 days, and then 20 mg/kg/day for an additi onal 7 days; no drug was given to the control group. NA levels were me asured at various times by ELISA, using guinea pig platelets extracts as the target. Splenectomy alone led to a significant decrease from th e control levels of NA; titers were further reduced by the plasma exch anges. In the absence of RS-61443, NA titers rose steadily, starting a t 24 hr after the last plasma exchange. In contrast, administration of RS-61443 resulted in levels of NA on day 7 not significantly differen t from those after plasma exchange, reducing the dose of RS-61443 to t he 20 mg/kg/day level during week 2 allowed the gradual return of NA. Administration of RS-61443 at the 40 mg/kg/day dose to rats after sple nectomy alone led to a clear and significant further decrease in NA le vels over the first week. It has been shown that RS-61443 can be admin istered for longer periods. The data presented suggest that use of thi s drug, perhaps with more conventional agents, may allow suppression o f NA for a significant period after transplantation.