Xenograft accommodation is accompanied by intragraft Th2 cytokines and vascular expression of protective genes

Abstract: We have studied the accommodation (survival of an organ graft in the presence of anti‐graft antibodies and complement) of heterotopic Golden Syrian hamster heart xenografts transplanted to Lewis rat recipients. The rats were treated with cyclosporine A (15 mg/kg/day i.m.) for the duration of the experiment and for 11 days with cobra venom factor. This regimen resulted in long‐term xenograft survival in approximately 75% of cases. Analysis of endothelial cells (and smooth muscle cells) in long‐surviving grafts showed expression of “protective” genes: A20, Bcl‐xL, Bcl‐2, and hemoxygenase, which we define as genes that prevent endothelial cells from undergoing responses that might lead to graft rejection. Surviving xenografts were also associated with intragraft Th2 cytokine expression. Rejected grafts did not express the protective genes and had a Thl pattern of cytokine expression. These studies indicate a potential mechanism linking molecular and cellular responses to development of xenograft accommodation.

[1]  C. Ferran,et al.  Protective genes expressed in endothelial cells: a regulatory response to injury. , 1997, Immunology today.

[2]  R. Coffman,et al.  Multiple Pathways for the Initiation of T Helper 2 (Th2) Responses , 1997, The Journal of experimental medicine.

[3]  J. Kovarik,et al.  Cellular rejection of fetal pancreas grafts: Differences between alio‐ and xenograft rejection , 1997 .

[4]  O. Korsgren.  Acute cellular xenograft rejection , 1997 .

[5]  D. Candinas,et al.  Accommodation of vascularized xenografts: Expression of “protective genes” by donor endothelial cells in a host Th2 cytokine environment , 1997, Nature Medicine.

[6]  J. Bluestone,et al.  CD28 costimulation promotes the production of Th2 cytokines. , 1997, Journal of immunology.

[7]  S. Constant,et al.  Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. , 1997, Annual review of immunology.

[8]  P. Linsley,et al.  Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Candinas,et al.  Protective genes expressed in endothelial cells of second hamster heart transplants to rats carrying an accommodated first graft , 1996 .

[10]  G. Cooper,et al.  Activation of the CPP32 Apoptotic Protease by Distinct Signaling Pathways with Differential Sensitivity to Bcl-xL* , 1996, The Journal of Biological Chemistry.

[11]  C. Ferran,et al.  A20 Blocks Endothelial Cell Activation through a NF-κB-dependent Mechanism* , 1996, The Journal of Biological Chemistry.

[12]  B. Benson,et al.  Human IgM xenoreactive natural antibodies can induce resistance of porcine endothelial cells to complement‐mediated injury , 1996 .

[13]  D. Willis,et al.  Heme oxygenase: A novel target for the modulation of inflammatory response , 1996, Nature Medicine.

[14]  J. Jessurun,et al.  Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro. , 1995, The American journal of pathology.

[15]  J. Wallwork,et al.  EVIDENCE THAT LONG‐TERM SURVIVAL OF CONCORDANT XENOGRAFTS IS ACHIEVED BY INHIBITION OF ANTISPECIES ANTIBODY PRODUCTION , 1992, Transplantation.

[16]  J. Platt,et al.  Cardiac xenografting in the pig-to-rhesus monkey model: manipulation of antiendothelial antibody prolongs survival. , 1992, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[17]  J. Platt,et al.  Accommodation: a working paradigm for progressing toward clinical discordant xenografting. , 1991, Transplantation proceedings.

[18]  F. Thompson,et al.  Renal transplantation across the ABO barrier--a 9-year experience. , 1990, Transplantation proceedings.

[19]  J. Squifflet,et al.  Present experiences in a series of 26 ABO-incompatible living donor renal allografts. , 1987, Transplantation proceedings.

[20]  J. Squifflet,et al.  Human ABO-incompatible living donor renal homografts. , 1985, The Netherlands journal of medicine.

[21]  M. Slapak,et al.  RENAL TRANSPLANT IN A PATIENT WITH MAJOR DONOR‐RECIPIENT BLOOD GROUP INCOMPATIBILITY: REVERSAL OF ACUTE REJECTION BY THE USE OF MODIFIED PLASMAPHERESIS , 1981, Transplantation.

[22]  K Ono,et al.  Improved technique of heart transplantation in rats. , 1969, The Journal of thoracic and cardiovascular surgery.