Abstract

BACKGROUND
Mixed chimerism is an effective approach for tolerance induction in transplantation. Strategies to achieve mixed chimerism with relatively low toxicity have significantly expanded the clinical use of chimerism.
METHODS
Allogeneic bone marrow transplants were performed between B6 (H2(b)) and BALB/c (H2(d)) mice. Recipient B6 mice were nonmyeloablatively conditioned with anti-αβ-T-cell receptor, anti-CD154, or rapamycin alone or in different combinations. A total of 15 × 10(6) BALB/c bone marrow cells were transplanted after varying doses of cGy of total body irradiation.
RESULTS
Pretreatment of recipients with anti-CD154 and rapamycin with or without T-cell lymphodepletion reduced the total body irradiation requirement to 100 cGy for establishing stable mixed chimerism. The mixed chimeras accepted donor islet allografts long term. Lymphocytes from mixed chimeras did not respond to host or donor antigens, yet were reactive to major histocompatibility complex-disparate third-party alloantigens, demonstrating functional donor-specific T-cell tolerance. No antibodies against donor and host were detected in mixed chimeras, suggesting humoral tolerance. Mixed chimeras showed no cytotoxicity to donor cells, but a similar rapid killing rate for major histocompatibility complex disparate third-party B10.BR cells compared with T-cell-deficient and wild-type controls in in vivo cytotoxicity assays, suggesting donor-specific tolerance in the innate immune cells was achieved in mixed chimeras.
CONCLUSIONS
Mixed chimeras prepared with low-intensity nonmyeloablative conditioning exhibit systemic tolerance in innate immunity and tolerance in adaptive T- and B-cell immune responses.

Links

Publisher Full Text

Authors

Xu H, Zhu Z, Huang Y, Bozulic LD, Hussain LR, Yan J, Ildstad ST

Institution

Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202-1760, USA.

Source

Transplantation 93:5 2012 Mar 15 pg 469-76

MeSH

Adaptive Immunity
Animals
Antibodies, Monoclonal
B-Lymphocytes
Bone Marrow Transplantation
CD40 Ligand
Graft Rejection
Graft Survival
Immune Tolerance
Immunity, Humoral
Immunity, Innate
Immunosuppressive Agents
Islets of Langerhans Transplantation
Lymphocyte Culture Test, Mixed
Lymphocyte Depletion
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Receptors, Antigen, T-Cell, alpha-beta
Sirolimus
Skin Transplantation
T-Lymphocytes
Time Factors
Transplantation Chimera
Transplantation Conditioning
Transplantation, Homologous
Whole-Body Irradiation

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

22228418