Regulatory T Cells Are Critical to Tolerance Induction in Presensitized Mouse Transplant Recipients Through Targeting Memory T Cells

被引：30

作者：

Ge, W. ^{[1
]}

Jiang, J. ^{[2
]}

Liu, W. ^{[2
,3
]}

Lian, D. ^{[2
]}

Saito, A. ^{[1
]}

Garcia, B. ^{[3
]}

Li, X. C. ^{[5
]}

Wang, H. ^{[1
,2
,3
,4
]}

机构：

[1] Univ Western Ontario, Dept Surg, London, ON N6A 3K7, Canada

[2] Univ Hosp, London Hlth Sci Ctr, Multiorgan Transplant Program, London, ON, Canada

[3] Univ Western Ontario, Dept Pathol, London, ON N6A 3K7, Canada

[4] London Hlth Sci Ctr, Lawson Hlth Res Inst, London, ON, Canada

[5] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

来源：

AMERICAN JOURNAL OF TRANSPLANTATION | 2010年 / 10卷 / 08期

基金：

加拿大创新基金会;

关键词：

Allograft tolerance; memory T cells; regulatory T cells; sensitized recipients; transplantation; CARDIAC ALLOGRAFT SURVIVAL; ACUTE XENOGRAFT REJECTION; ANTI-CD45RB MONOCLONAL-ANTIBODY; OX40-OX40 LIGAND INTERACTION; TOLEROGENIC DENDRITIC CELLS; OX40; LIGAND; IN-VIVO; CYCLOSPORINE THERAPY; ALLOIMMUNE RESPONSES; MEDIATED REJECTION;

D O I：

10.1111/j.1600-6143.2010.03186.x

中图分类号：

R61 [外科手术学];

学科分类号：

摘要：

Memory T cells are a significant barrier to induction of transplant tolerance. However, reliable means to target alloreactive memory T cells have remained elusive. In this study, presensitization of BALB/c mice with C57BL/6 skin grafts generated a large number of OX40+CD44hieffector/memory T cells and resulted in rapid rejection of donor heart allografts. Recognizing that anti-OX40L monoclonal antibody (mAb) (alpha-OX40L) monotherapy prolonged graft survival through inhibition and apoptosis of memory T cells in presensitized recipients, alpha-OX40L was added to the combined treatment protocol of LF15-0195 (LF) and anti-CD45RB (alpha-CD45RB) mAb-a protocol that induced heart allograft tolerance in non-presensitized recipients but failed to induce tolerance in presensitized recipients. Interestingly, this triple therapy restored donor-specific heart allograft tolerance in our presensitized model that was associated with induction of tolerogenic dendritic cells and CD4+CD25+Foxp3+ T regulatory cells (Tregs). Of note, CD25+ T cell depletion in triple therapy recipients prevented establishment of allograft tolerance. In addition, adoptive transfer of donor-primed effector/memory T cells into tolerant recipients markedly reduced levels of Tregs and broke tolerance. Our findings indicated that targeting memory T cells, by blocking OX40 costimulation in presensitized recipients was very important to expansion of Tregs, which proved critical to development of tolerance.

引用

页码：1760 / 1773

页数：14

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