Biomedical subjects

Jian-Guo Chai

Publications and source records attributed to Jian-Guo Chai.

6 recordsLinked to original sources

PubMed2005

Regulatory T cells, derived from naïve CD4+CD25- T cells by in vitro Foxp3 gene transfer, can induce transplantation tolerance.

BACKGROUND: Regulatory T (Treg) cells, generated in vitro by Foxp3 gene transfer into naive CD4+25- T cells, have been shown to inhibit the development of inflammation and autoimmune disease, but it is not known whether they are able to prevent allograft rejection. This study investigated whether Treg cells generated from naive CD4+ T cells by Foxp3 gene transfer could induce transplantation tolerance. METHODS: HY-specific, T-cell receptor (TCR)-transgenic CD4+25- T cells were retrovirally transduced with the Foxp3 gene. The phenotype, function, and cytokine profiles of the transduced cells were examined in vitro by fluorescence-activated cell sorter, T-cell proliferation assays, enzyme-linked immunosorbent assay, and intracellular cytokine staining. Adoptive transfer and skin grafting experiments were conducted to assess whether Foxp3-transduced HY-specific T cells could prevent the rejection of syngeneic male grafts. RESULTS: CD4+25- T cells retrovirally transduced with Foxp3 express a panel of cell surface and intracellular molecules closely associated with Treg activity. This Treg phenotype was stable during in vitro culture with some further maturation. In vitro, Foxp3-transduced cells were functionally anergic and suppressive T cells. In vivo adoptive transfer of Foxp3-transduced HY-specific TCR-transgenic CD4+ T cells protected male skin grafts from rejection by syngeneic females. Retroviral transduction of the Foxp3 gene into non-TCR-transgenic CD4+25- T cells, however, had no influence on male skin graft rejection. CONCLUSION: This study provides the first evidence that Foxp3-transduced T cells can control the rejection of an allogeneic transplant and suggests that T-cell Foxp3 gene transfer may have therapeutic value in clinical transplantation.

Animals↗

PubMed2005

Mixed-haplotype MHC class II molecules select functional CD4+ T cells.

MHC class II molecules are formed from polymorphic alpha and beta chains. While pairing of chains is most efficient within class II isotypes and haplotypes, limited pairing and surface expression of mixed-haplotype and -isotype class II molecules is common. The function of such molecules in antigen presentation has been established by the unique restriction of responses in F1 mice. However, it has not been established whether mixed class II molecules are able to mediate selection of functional T cells and how the reduced avidity of the TCR/MHC interaction influences the repertoire. In this report we have addressed these issues through the production of mice expressing solely mixed-haplotype class II molecules. The mixed class II molecules promote selection of a small CD4+ T cell repertoire with modified TCR use. The selected CD4+ T cells are functional in vivo and in vitro.

Amino Acid Sequence↗

PubMed2004

Transplantation tolerance induced by intranasal administration of HY peptides.

Induction of antigen-specific tolerance to transplantation antigens is desirable to control host-versus-graft and graft-versus-host reactions. Following molecular identification of a set of minor histocompatibility (H) antigens, we have used selected HY peptide epitopes for this purpose. Intranasal administration of individual major histocompatibility complex (MHC) class II-restricted HY peptides induces indefinite survival of syngeneic male skin grafts and allows engraftment of male bone marrow. Tolerance involves linked suppression to additional HY epitopes on test grafts. Long-term tolerance also requires suppression of emerging thymic emigrants. It does not involve deletion. HY peptide-specific CD4(+) and CD8(+) T cells expand on re-exposure to male antigen; these expansions are smaller in tolerant than control mice and fewer HY-specific cells from tolerant females secrete interferon gamma and interleukin 10 (IL-10). Significantly, CD4(+) cells from peptide-pretreated females fail to make IL-2 responses to cognate peptide, limiting expansion of the HY-specific CD8(+) populations that can cause graft rejection. Consistent with this, tolerance induction by HY peptide is abrogated by coadministration of lipopolysaccharide. IL-10 does not appear to be critically involved because tolerance is inducible in IL-10-deficient mice. Adoptive transfer of tolerance into naive neonatal recipients by splenocytes from long-term tolerant donors provides evidence for involvement of regulatory cells.

Administration, Intranasal↗

PubMed2003

Multiparity induces priming to male-specific minor histocompatibility antigen, HY, in mice and humans.

One of the factors that increases the risk of graft-versus-host disease following allogeneic stem cell transplantation is the use of multiparous females as donors. Since minor histocompatibility (H) antigens are the main targets of graft-versus-host and graft-versus-leukemia responses, we tested the hypothesis that multiparity could prime minor H antigen-specific T cells. We examined the peripheral lymphoid populations of multiparous mice and humans for evidence of priming of CD8+ T-cytotoxic lymphocytes against peptide epitopes of the male-specific minor H antigen, HY. In contrast to naive females, multiparous females have measurable levels of circulating HY-specific tetramer-positive T lymphocytes, which can be readily expanded in vitro. These findings have implications for the in vitro generation of T-cell clones as reagents for immunotherapy for tumors following stem cell transplantation.

Animals↗

PubMed2002

CD4+CD25+ T cells as immunoregulatory T cells in vitro.

We have further characterized the in vitro phenotype and function of anergic and suppressive CD4(+)25(+) T cells. Following TCR ligation, DO.11.10 CD4(+)25(+) T cells suppress the activation of OT-1 CD8(+)25(-) T cells in an antigen nonspecific manner. Although suppression was seen when using a mixture of APC from both parental strains, it was very much more marked when using F1 APC. APC pretreated with, and then separated from CD4(+)25(+) T cells did not have diminished T cell costimulatory function, suggesting that APC are not the direct targets of CD4(+)25(+) T cell regulation. CTLA-4 blockade failed to abrogate suppression by CD4(+)25(+) T cells in mixing experiments. Although CD4(+)25(+) T cells failed to respond following cross-linking of TCR, they could be induced to proliferate following the addition of exogenous IL-2, allowing the generation of a T cell line from CD4(+)25(+) T cells. After the first in vitro restimulation, CD4(+)25(+) T cells were still anergic and suppressive following TCR engagement. However, after three rounds of restimulation, their anergic and suppressive status was abrogated.

Abatacept↗

PubMed2002

HY peptides modulate transplantation responses to skin allografts.

Injection of female C57BL/6 mice with immature female bone marrow-derived dendritic cells (BMDC) pulsed with a single immunodominant HY(Db) Uty peptide, WMHHNMDLI, induces prolonged survival of syngeneic male skin grafts. In contrast, injection of immature female BMDC pulsed with a single MHC class I-restricted HY(Ab) Dby peptide, NAGFNSNRANSSRSS, causes immunization similar to that following injection of male cells. Tolerance induced by HY(Db) Uty peptide pretreatment is not characterized by clonal deletion: long-term tolerant mice maintain circulating HY(Db) Uty tetramer(+) T cells which expand following exposure to male cells in vivo or in vitro. Tolerance to male skin grafts can be adoptively transferred into neonatal females with splenocytes from tolerant donors. Tolerance is specific-third-party skin grafts are rejected. We propose that tolerance in this model is initiated by cognate interaction of HY(Db) Uty-specific CD8(+) T cells with their ligand, presented either on the injected immature BMDC or on recipient DC. This interaction leads to incomplete activation of the CD8(+) T cells resulting in diminished responsiveness of CD4(+) and CD8(+) T cells specific for HY peptide epitopes subsequently presented on the male graft.

Animals↗