title: Th1 cytokines, programmed cell death, and alloreactive T cell clone size in transplant tolerance.
abstract: The Th1 cytokines IL-2 and IFN-gamma, which inhibit T cell proliferation and promote activation induced cell death, may be required to diminish alloreactive T cell numbers and to foster tolerance across full allogeneic barriers. However, we hypothesized that these cytokines might be dispensable when the alloreactive T cell clone size is relatively small, as is seen in recipients of minor-mismatched grafts. We show that alloreactive T cell clone size of C57BL/6 mice against multiple minor-mismatched 129X1/sv mice was approximately 4-9-fold smaller than that against MHC-mismatched BALB/c mice. In the MHC-mismatched combination, CD28-B7 blockade by CTLA4Ig induced long-term graft survival in wild-type recipients, but this treatment was ineffective in IFNgamma(-/-) or IL-2(-/-) recipients. In contrast, in the minor-mismatched combination, CTLA4Ig induced long-term allograft survival in wild-type, IFNgamma(-/-), and IL-2(-/-) recipients. Bcl-x(L) transgenic animals, which are defective in "passive" T cell death, are likewise sensitive to the effects of CTLA4Ig only in the setting of the minor-mismatch grafts. Therefore, the alloreactive T cell clone size is an important determinant affecting the need for Th1 cytokines and T cell death in tolerance induction. These data have implications for the design of tolerance strategies in transplant recipients with varying degrees of MHC mismatching.
authors.affiliation: Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Kishimoto
authors.forename: Sigrid
authors.initials: S
authors.lastname: Sandner
authors.forename: Jaime
authors.initials: J
authors.lastname: Imitola
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sho
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Li
authors.forename: Peter B
authors.initials: PB
authors.lastname: Langmuir
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis; D023201:CD40 Ligand / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013045:Species Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D018417:Th1 Cells / Q000473:pathology*; D013997:Time Factors; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D007376:Interleukin-2; D023201:CD40 Ligand; D007371:Interferon-gamma