Dissociation between peripheral blood chimerism and tolerance to hindlimb composite tissue transplants: preferential localization of chimerism in donor bone.
BACKGROUND
Mixed chimerism induces donor-specific tolerance to composite tissue allotransplants (CTAs). In the present studies, we used a nonmyeloablative conditioning approach to establish chimerism and promote CTA acceptance.


METHODS
Wistar Furth (RT1A(u)) rats were conditioned with 600 to 300 cGy total body irradiation (TBI, day-1), and 100 x 10(6) T-cell-depleted ACI (RT1A(abl)) bone marrow cells were transplanted on day 0, followed by a 11-day course of tacrolimus and one dose of antilymphocyte serum (day 10). Heterotopic osteomyocutaneous flap transplantation was performed 4 to 6 weeks after bone marrow transplantation.


RESULTS
Mixed chimerism was initially achieved in almost all recipients, but long-term acceptance of CTA was only achieved in rats treated with 600 cGy TBI. When anti-alphabeta-T-cell receptor (TCR) monoclonal antibody (mAb) (day-3) was added into the regimens, donor chimerism was similar to recipients preconditioned without anti-alphabeta-TCR mAb. However, the long-term CTA survival was significantly improved in chimeras receiving more than or equal to 300 cGy TBI plus anti-alphabeta-TCR mAb. Higher levels of donor chimerism were associated with CTA acceptance. The majority of flap acceptors lost peripheral blood chimerism within 6 months. However, donor chimerism persisted in the transplanted bone at significantly higher levels compared with other hematopoietic compartments. The compartment donor chimerism may be responsible for the maintenance of tolerance to CTA. Long-term acceptors were tolerant to a donor skin graft challenge even in the absence of peripheral blood chimerism.


CONCLUSIONS
Mixed chimerism established by nonmyeloablative conditioning induces long-term acceptance of CTA, which is associated with persistent chimerism preferentially in the transplanted donor bone.
Rahhal
Dina N
DN
Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202-1760, USA. stilds01@gwise.louisville.edu
Xu
Hong
H
Huang
Wei-Chao
WC
Wu
Shengli
S
Wen
Yujie
Y
Huang
Yiming
Y
Ildstad
Suzanne T
ST
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D016025:Bone Transplantation / Q000276:immunology*; D001842:Bone and Bones / Q000276:immunology*; D006614:Hindlimb / Q000601:surgery; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011920:Rats, Inbred WF; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D013524:Surgical Flaps; D013997:Time Factors; D014019:Tissue Donors; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous; D019737:Transplants; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D016693:Receptors, Antigen, T-Cell, alpha-beta