SV40 Infection Associated With Rituximab Treatment After Kidney Transplantation in Nonhuman Primates.

BACKGROUND.: A regimen consisting of polyclonal anti-T-cell antibody, sirolimus (SRL), and donor bone marrow (DBM) infusion induces robust transplantation tolerance to skin allografts in mice. We investigated the effect of a similar regimen in a nonhuman primate (NHP) model. METHODS.: Cynomolgus macaques (Macaca fascicularis) were transplanted with mismatched kidney allografts. Recipients were treated with 7 doses of antithymocyte globulin (Thymoglobulin, day 1 to 9), sirolimus, and DBM infusion (day 14). Anti-CD20 antibody, rituximab, was given on days 0 and 5. RESULTS.: A regimen of Thymoglobulin, 30 days of SRL, and DBM infusion induced significantly greater prolongation of graft survival with a mean survival time of 88 days compared with the control regimen (no DBM) with an mean survival time of 53 days (P=0.022). Unlike the murine skin allograft model, all grafts were rejected within 111 days. A combination of Thymoglobulin, continuous SRL, and rituximab caused graft and systemic SV40 infection and failed to achieve further extension of graft survival. C4d deposition was observed in 50% of recipients as early as 18 days, suggesting antidonor antibody production. A transient, low-to-moderate degrees of multilineage chimerism was observed after DBM infusion. Treatment with Thymoglobulin resulted in profound depletion of CD4 and CD8 T cells, whereas addition of rituximab achieved prolonged (up to 3 months) depletion of CD20 B cells. CONCLUSION.: The Thymoglobulin, SRL, and DBM protocol is simple and produces long-term kidney allograft survival in NHP although additional treatment modalities may be necessary for induction of long-term tolerance.

Maki T, Carville A, Stillman IE, Sato K, Kodaka T, Minamimura K, Ogawa N, Kanamoto A, Gottschalk R, Monaco AP, Marr-Belvin A, Westmoreland SV, Sehgal P.

1The Transplant Center, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA. 2 New England Primate Research Center, Harvard Medical School, Framingham, MA. 3 Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.