MEMORY AND REGULATORY T CELLS FOLLOWING T CELL DEPLETION IN TRANSPLANTATION

Emory University, Atlanta GA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lymphocyte depletion acutely lowers the overall number of T cells in an attempt to dampen rejection to allograft. Unfortunately, these same depleting agents promote T effector/memory cell repopulation through a combination of memory T cell sparing, homeostatic proliferation, and immune activation on memory-dominated recovery. In this study, we defined the role these factors play in lymphopenia-induced memory T cell expansion, and further describe the ability of short-term tacrolimus or sirolimus treatment to delay rejection. Rhesus macaques were selected as pairs based on MHC Class I typing, CFSE-based mixed lymphocyte response and their FN18 positivity. Following renal transplantation with native nephrectomy, animals were treated with either CD3-Immunotoxin alone (0.025mg/kg/dose, BID for 4 days), or treated in combination with tacrolimus or sirolimus. Complete blood count and T cell phenotype was monitored by flow cytometrical analysis. Compared to untreated controls, CD3-IT treated animals showed significantly increased graft survival (6.5 vs. 12 days). Significant T cell depletion was observed, and was maximal at day 4 (99.3 0.1% depletion). However, unlike chemically conjugated (CRM9-FN18) CD3-IT, this new recombinant CD3-IT (A-dmDT390-scfbDb) showed rapid repopulation of T cells (92.9 1.6% depletion) within a week, with proportional phenotypic transformation into CD28lowCD95intCD8 T cells and CD28hiCD95hiCD4 T cells. CD8 T cells with effector memory (61.2 5.7 vs. 40.8 6.2;p0.05) and CD4 T cell with central memory phenotype (61.9 10.1 vs. 14.0 4.8;p0.05) reached numbers that were consistently higher than pre-treatment. Furthermore, we observed incomplete depletion (73.9 17.7%;n=2) of T cells in lymph nodes compared to the peripheral blood (93.8 0.9%;n=5) at 1 wk. Both tacrolimus and sirolimus maintenance delayed the pace of T cell memory phenotypic changes, but did not ultimately prevent acute rejection. Further studies are necessary to improve the potential role of rCD3-IT to prevent acute cellular rejection.