Rat cytomegalovirus infection interferes with anti-CD4 mAb-(RIB 5/2) mediated tolerance and induces chronic allograft damage.
In order to assess the role of heterologous immunity on tolerance induction (TI) by signal 1 modification, the influence of rat cytomegalovirus infection (RCMVI) on TI by a non-depleting monoclonal anti-CD4 mAb (monoclonal antibody) (RIB 5/2) in a rat kidney transplant (KTx) model was investigated. Orthotopic rat KTx (Dark Agouty (DA)-->Lewis (LEW)) was performed after TI with RIB 5/2 [10 mg/kg body weight (BW); day -1, 0, 1, 2, 3; i.p. (intraperitoneal route)]. RCMVI (5x10E5 Plaque forming units [PFU] i.p.) was simultaneously conducted to KTx, 50 days after KTx, and 14 days before and after KTx. RIB 5/2 induced robust allograft tolerance even across the high-responder strain barrier. RCMVI broke RIB 5/2-induced tolerance regardless of the time of RCMVI but did not induce acute graft failure during the 120 days follow-up. RCMVI induced a significant chronic deterioration of allograft function (p<0.01) and enhanced morphological signs of chronic allograft damage (p<0.05). Cellular infiltrates and major histo-compatibility complex (MHC)-expression were more pronounced (p<0.05) in the infected groups. RCMVI induced not only RCMV-specific T-cell response but also enhanced the frequency of alloreactive T cells. RCMV interferes with anti-CD4 mAb-induced tolerance and leads to chronic allograft damage. The data we presented suggest a potentially important role of viral infections and their prophylaxis in clinical TI protocols.
Pascher
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A
Department of Visceral- and Transplantation Surgery, Charité- Universitaetsmedizin Berlin, Campus Virchow, Berlin, Germany, and Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, MA, USA. andreas.pascher@charite.de
Proesch
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S
Pratschke
J
J
Reutzel-Selke
A
A
Sawitzki
B
B
Lehmann
M
M
Tullius
S G
SG
Neuhaus
P
P
Volk
H-D
HD
Reinke
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000276:immunology*; D002908:Chronic Disease; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000821:virology; D006085:Graft Survival; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007674:Kidney Diseases / Q000276:immunology* / Q000821:virology; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D018146:Muromegalovirus / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000473:pathology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; C108171:RIB 5-2 monoclonal antibody