Biomedical subjects

Ling Tian

Publications and source records attributed to Ling Tian.

57 records · Page 4Linked to original sources

PubMed2002

Allochimeric class I MHC protein-induced tolerance by partial TCR engagement requires activation of both CTL4- and common gamma-chain-dependent cytokine signals.

BACKGROUND: The various toxicities associated with the general immune suppression resulting from current clinical immunosuppressive therapies continue to plague transplant recipients as well as jeopardize allograft survival. METHODS: The present study utilized allochimeric class I MHC antigens (alpha1hu70-77-RT1.Aa) bearing only four donor RT1.Au polymorphic amino acids (a.a.; His70, Val73, Asn74, and Asn77) superimposed on the recipient RT1.Aa background to induce transplantation tolerance in the rat cardiac transplant model. RESULTS: Oral delivery of alpha1hu70-77-RT1.Aa protein alone (days 0-6) induced tolerance, as evidenced by inhibition of both acute and chronic rejection processes. Delivery of alpha1hu70-77-RT1.Aa with therapeutic doses of cyclosporine (CsA) also prevented chronic rejection, otherwise readily developed after treatment with CsA alone. A polymerase chain reaction (PCR)-based analysis showed that tolerant recipients had reduced numbers of interleukin (IL)-2/interferon (IFN)-gamma-producing T helper (Th)1 cells and elevated numbers of IL-4/IL-10-producing Th2 cells. Adoptive transfer experiments revealed that potent regulatory T cells mediated tolerance. The same T cells displayed diminished T cell receptor (TCR)-driven signaling via extracellular regulated kinase, AP-1, and NF-kappaB, as well as the common gamma-chain (gammac) cytokine-receptor-induced signaling by Janus kinase 3 (Jak3)/stimulators and activators of transcription Stat/5 pathways. Tolerance induction was prevented in vivo by inhibition of signal 2 by CTL4Ig or of signal 3 by either rapamycin, which disrupts the mammalian target of rapamycin, or AG490, which inhibits Jak3. Finally, partial or complete tyrosine phosphorylation of Zap70 was observed in alloantigen-specific T cell clones in response to tolerogenic versus immunogenic peptides, respectively. CONCLUSIONS: Tolerance induction by allochimeric proteins is achieved by partial TCR activation in the presence of signals 2 and 3, resulting in a skewed Th2 phenotype.

Abatacept↗

PubMed2002

Immunogene therapy of tumors with a vaccine based on the ligand-binding domain of chicken homologous integrin beta3.

The breaking of immune tolerance against angiogenesis-associated molecules should be a useful approach for cancer therapy by active immunity. We used chicken integrin beta3 as a model antigen to explore the feasibility of immunogene therapy of the tumors with a vaccine based on a single xenogeneic homologous gene, targeting the molecules associated with angiogenesis. To test this concept we constructed a plasmid DNA encoding the ligand-binding domain of chicken integrin beta3 (P-BD-C) and control vectors. We found that immunogene therapy of tumors with a vaccine based on the ligand-binding domain of chicken integrin beta3 (P-BD-C) was effective in both protective and therapeutic anti-tumor immunity in several tumor models in mice. Autoantibodies against integrin beta3 in sera of mice immunized with the ligand-binding domain of chicken integrin beta3 could be found by Western blot analysis and ELISA assay. The purified immunoglobulins were effective in the inhibition of endothelial cell proliferation in vitro, and in anti-tumor activity as well as in the inhibition of angiogenesis by adoptive transfer in vivo. The anti-tumor activity and the production of integrin beta3-specific autoantibodies (manifested by significantly elevated Ig G1 and Ig G2b) could be abrogated by the depletion of CD4+ T lymphocytes. These observations may provide a vaccine strategy for cancer therapy through the induction of the autoimmunity against the molecules associated with tumor growth in a cross-reaction with a single xenogeneic homologous gene and may be of importance in the further exploration of the applications of other xenogeneic homologous genes identified in human and other animal genome sequence projects in cancer therapy.

Animals↗

PubMedDate not supplied

Active antitumor immunity elicited by vaccine based on recombinant form of epidermal growth factor receptor.

Active immunotherapy targeting epidermal growth factor receptor (EGFR) should be another attractive approach to the treatment of EGFR-positive tumors. To test this concept, the authors evaluated the potential immune responses and antitumor activities elicited by dendritic cells pulsed with recombinant ectodomain of mouse EGFR (DC-edMER). Spleen cells isolated from DC-edMER-vaccinated mice showed a high quantity of EGFR-specific antibody-producing cells. EGFR-reactive antibody in sera isolated from vaccinated mice was identified and shown to be effective against tumors in vitro and in vivo by adoptive transfer. DC-edMER vaccine also elicited cytotoxic T-lymphocyte responses that could mediate antitumor effects in vitro and adoptive transfer in vivo. In addition, EGFR-specific cytokines responses were elicited by DC-edMER vaccine. Immunization with DC-edMER resulted in tumor regression and prolonged survival in mice challenged with Lewis lung carcinomas and mammary cancer models. Depletion of CD4+ T lymphocytes could completely abrogate the antitumor activity and EGFR-specific antibody responses, whereas the depletion of CD8+ T lymphocytes showed partial abrogation of the antitumor activity but antibody was still detected. Furthermore, tumor-induced angiogenesis was suppressed in DC-edMER-vaccinated mice or mice treated with antibody adoptive transfer. Taken together, these findings suggest the antitumor immunity could be induced by DC-edMER, which may involve both humoral and cellular immunity, and may provide insight into the treatment of EGFR-positive tumors through the induction of active immunity against EGFR.

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