Mukherjee Rinee, Chaturvedi Pratibha, Qin Hui-Yu, Singh Bhagirath
Department of Microbiology and Immunology, University of Western Ontario, and John P. Robarts Research Institute, University of Western Ontario, London, N6A 5C1, Ontario, Canada.
J Autoimmun. 2003 Nov;21(3):221-37. doi: 10.1016/s0896-8411(03)00114-8.
NOD mice have a relative deficiency of CD4+CD25+ regulatory T cells that could result in an inability to maintain peripheral tolerance. The aim of this study was to induce the generation of CD4+CD25+ regulatory T cells in response to autoantigens to prevent type 1 diabetes (T1D). We found that immunization of NOD mice with insulin B-chain peptide B:9-23 followed by 72 h in vitro culture with B:9-23 peptide induces generation of CD4+CD25+ regulatory T cells. Route of immunization has a critical role in the generation of these cells. Non-autoimmune mice BALB/c, C57BL/6 and NOR did not show up regulation of CD4+CD25+ regulatory T cells. These cells secreted large amounts of TGF-beta and TNF-alpha with little or no IFN-gamma and IL-10. Adoptive transfer of these CD4+CD25+ regulatory T cells into NOD-SCID mice completely prevented the adoptive transfer of disease by diabetogenic T cells. Although, non-self antigenic OVA (323-339) peptide immunization and in vitro culture with OVA (323-339) peptide does result in up regulation of CD4+CD25+ T cells, these cells did not prevent transfer of diabetes. Our study for the first time identified the generation of antigen-specific CD4+CD25+ regulatory T cells specifically in response to immunization with B:9-23 peptide in NOD mice that are capable of blocking adoptive transfer of diabetes. Our results suggest the possibility of using autoantigens to induce antigen-specific regulatory T cells to prevent and regulate autoimmune diabetes.
非肥胖型糖尿病（NOD）小鼠的CD4+CD25+调节性T细胞相对缺乏，这可能导致无法维持外周耐受。本研究的目的是诱导针对自身抗原产生CD4+CD25+调节性T细胞，以预防1型糖尿病（T1D）。我们发现，用胰岛素B链肽B:9-23免疫NOD小鼠，然后与B:9-23肽进行72小时体外培养，可诱导产生CD4+CD25+调节性T细胞。免疫途径在这些细胞的产生中起关键作用。非自身免疫性小鼠BALB/c、C57BL/6和NOR未出现CD4+CD25+调节性T细胞的上调。这些细胞分泌大量转化生长因子-β（TGF-β）和肿瘤坏死因子-α（TNF-α），几乎不分泌或不分泌干扰素-γ（IFN-γ）和白细胞介素-10（IL-10）。将这些CD4+CD25+调节性T细胞过继转移到NOD-SCID小鼠中，可完全阻止致糖尿病T细胞的疾病过继转移。虽然，用非自身抗原性卵清蛋白（OVA）（323-339）肽免疫并与OVA（323-339）肽进行体外培养确实会导致CD4+CD25+T细胞上调，但这些细胞并不能阻止糖尿病的转移。我们的研究首次确定，在NOD小鼠中，用B:9-23肽免疫可特异性诱导产生抗原特异性CD4+CD25+调节性T细胞，这些细胞能够阻止糖尿病的过继转移。我们的结果表明，利用自身抗原诱导抗原特异性调节性T细胞来预防和调节自身免疫性糖尿病是有可能的。
