Host thymectomy and cyclosporine lead to unstable skin graft tolerance after class I mismatched allogeneic neonatal thymic transplantation in mice.
BACKGROUND
Our laboratory has demonstrated that xenogeneic porcine thymus tissue grafted in thymectomized (ATX) and T cell-depleted mice induces donor-specific tolerance. Recipient thymectomy is essential for the success of tolerance induction. In contrast, studies in pigs grafted with non-vascularized allogeneic class I mismatched thymus tissue under the cover of CyA have shown that removal of host thymus is detrimental to thymic graft survival. To determine the requirements for nonvascularized allogeneic class I-mismatched thymic engraftment in mice, we performed thymic allotransplantation under the cover of CyA.


METHODS
Euthymic and ATX B10.MBR mice received class I mismatched B10.AKM neonatal mouse thymus (NMTHY) tissue under the kidney capsule with or without a short course of CyA. The grafts were allowed to engraft for two and a half months before exploratory laparotomy was performed to evaluate them. Three months after the thymic transplant, mice were challenged with donor-specific skin grafts to assess tolerance. One month after donor-specific skin grafting, they received third party B10.BR skin grafts. Cellular anti-donor immune responses were studied at the time of euthanasia.


RESULTS
CyA-treated ATX and euthymic control mice showed good engraftment of the allogeneic thymic tissue at the time of exploratory laparotomy, whereas non-CyA-treated ATX and euthymic controls had rejected the grafts. The CyA-treated ATX B10.MBR mice accepted donor-specific skin grafts, but rejected them following a challenge with third party B10.BR skin grafts. Untreated ATX and euthymic mice and 6 of 7 CyA-treated euthymic mice rejected donor skin within 15 days. Mixed lymphocyte reactions did not show an increased anti-donor response, but CML clearly showed sensitization and increased killing activity against donor-type targets in these mice.


CONCLUSIONS
Allogeneic thymic transplantation across a class I MHC barrier under the cover of CyA induces a metastable state of tolerance in mice. To achieve this state, ATX of the recipient is required.
Rodríguez-Barbosa
José-Ignacio
JI
Transplantation Biology Research Center, Bone Marrow Transplantation Section, Surgical Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
Haller
Gary W
GW
Zhao
Guiling
G
Sachs
David H
DH
Sykes
Megan
M
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D006648:Histocompatibility; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D016038:Skin Transplantation / Q000276:immunology; D013934:Thymectomy; D013950:Thymus Gland / Q000637:transplantation*; D023001:Transplantation Tolerance / Q000187:drug effects; D014184:Transplantation, Homologous
D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D016572:Cyclosporine