ANTI-MHC CLASS II MABS SUPPRESS ALLOGENEIC RESPONSES IN SOLID ORGAN TRANSPLANTATION IN MICE AND PRIMATES

Abstract

377 MHC class II molecules are critical recognition components of the cognate immune response, and thus an excellent target to alter the allograft response. We have investigated non-cell depleting monoclonal antibodies(Mabs) to MHC Class II and their effect on allograft survival in mice and non-human primates with a view to their use in human transplants. Heterotopic mouse heart transplants were performed from Balb/c(H-2d) to either Biozzi AB/H (KaI-Ag7I-E-Dq; n=6) or CBA (H-2k) mice and graft function assessed by palpation. Recipients received either cOX6γ1 (mouse anti-mouse anti-class II Mab, γ1 isotype) or MOPC21 (isotype matched control Mab) at 40 mg/kg IP on days -1, 0 and +1 only. The circulating T½ of cOX6γ1 is <24h. Median graft survival time was 39 days in Biozzi and 44 days in CBA, compared to 11 days in the control group. Studies were subsequently performed in a cynomolgus monkey model of renal transplantation. gLE1 Mab was used (a recombinant human anti-DR Mab that cross reacts with the mamu molecule in cynomolgus). This Mab is a modified human γ1 antibody with reduced ability to bind complement and interact with FcγR1 and has a circulating T½ < 4h. In the monkeys, IV gLE1 caused a transient decline in circulating B-cells (resolved by 48h) but no long term depletion of any leukocyte subset. Animals (n=5) were given gLE1 at 10 mg/kg on days -1, 0, +1 or -2h, and days 1 and 2, but no other concommitant therapy. Control animals received saline injections. Animals underwent bilateral native nephrectomy. The transplant kidney was placed intraabdominally with anastomosis to the aorta and vena cava. Renal function was monitored by serum creatinine, and animals sacrificed when severely uremic. gLE1-treated monkeys survived 14,24,24,27 and 28 days, with control survival of 6 and 8 days. Thus, a short treatment course of anti-class II Mabs results in marked prolongation of graft survival in both mice and non-human primates. The effect is not dependent upon cell depletion, and extends long beyond the persistence of the Mab in the circulation. It is unlikely for this to be due to passive blockade of the class II: TCR interaction, and may be related to the active suppression of the allogeneic response. This research was funded by Celltech Therapeutics, Ltd., Slough, U.K.