Variable relationship between chimerism and tolerance after hematopoietic cell transplantation without myelosuppressive conditioning.
BACKGROUND
We have previously described a mixed chimerism protocol that avoids myelosuppressive conditioning and permits hematopoietic cell transplantation across MHC barriers without the need for whole body irradiation in miniature swine. Here, we report our current experience including animals conditioned without thymic irradiation, and we attempt to define the relationship between long-term chimerism and stable tolerance in these animals.


METHODS
Recipient swine received in vivo T-cell depletion, with or without thymic irradiation on day -2. Cyclosporine was administered for 30 to 60 days beginning on day -1. A total of 1 to 2 x 10(10) /kg cytokine-mobilized donor hematopoietic cells were infused during 3 days. Chimerism was determined by flow cytometry. In vitro tolerance assays and donor-matched kidney transplantation were performed after cessation of cyclosporine.


RESULTS
Most recipients maintained stable chimerism (26 of 35) and were specifically tolerant to donor-matched cells in vitro regardless of whether they received thymic irradiation. Donor-matched kidney transplantations performed in chimeric animals without in vitro antidonor immune responses were accepted without immunosuppression. Some animals developed in vitro evidence of antidonor MHC responsiveness despite the persistence of donor cells in the peripheral blood. Donor-matched kidney transplantations performed in the face of these responses were rejected.


CONCLUSIONS
These data indicate that this nonmyelosuppressive protocol can induce stable chimerism and robust tolerance even in animals conditioned without thymic irradiation. However, the data also demonstrate that macrochimerism does not always correlate with tolerance. Lack of in vitro antidonor immune responses in chimeric animals is an important predictor of renal allograft acceptance in this model.
Gleit
Zachary L
ZL
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Fuchimoto
Yasushi
Y
Yamada
Kazuhiko
K
Melendy
Elizabeth
E
Scheier-Dolberg
Rachel
R
Monajati
Leila
L
Coburn
Rebecca C
RC
Neville
David M
DM
Sachs
David H
DH
Huang
Christene A
CA
D000818:Animals; D001790:Blood Physiological Phenomena; D001853:Bone Marrow / Q000502:physiology* / Q000503:physiopathology; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance; D016030:Kidney Transplantation / Q000276:immunology; D013552:Swine; D013556:Swine, Miniature; D013950:Thymus Gland / Q000503:physiopathology; D013997:Time Factors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014181:Transplantation Immunology; D014184:Transplantation, Homologous / Q000276:immunology