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.


CONCLUSIONS
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
Takashi
T
The Transplant Center, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. tmaki@bidmc.harvard.edu
Carville
Angela
A
Stillman
Isaac E
IE
Sato
Kanetoshi
K
Kodaka
Tetsuro
T
Minamimura
Keisuke
K
Ogawa
Norihiko
N
Kanamoto
Akira
A
Gottschalk
Rita
R
Monaco
Anthony P
AP
Marr-Belvin
Amanda
A
Westmoreland
Susan V
SV
Sehgal
Prabhat
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D001402:B-Lymphocytes / Q000276:immunology; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015935:Complement C4b / Q000032:analysis; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D018655:Lymphocyte Count; D008252:Macaca fascicularis; D010446:Peptide Fragments / Q000032:analysis; D027601:Polyomavirus Infections / Q000139:chemically induced* / Q000473:pathology; D000069283:Rituximab; D013539:Simian virus 40; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014412:Tumor Virus Infections / Q000139:chemically induced* / Q000473:pathology
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D010446:Peptide Fragments; D000069283:Rituximab; D015935:Complement C4b; C032261:complement C4d