Selective CD28 Blockade Attenuates Acute and Chronic Rejection of Murine Cardiac Allografts in a CTLA-4-Dependent Manner

被引：82

作者：

Zhang, T. ^{[1
,2
]}

Fresnay, S. ^{[1
]}

Welty, E. ^{[1
]}

Sangrampurkar, N. ^{[1
]}

Rybak, E. ^{[1
]}

Zhou, H. ^{[1
]}

Cheng, X. -F. ^{[1
]}

Feng, Q. ^{[1
]}

Avon, C. ^{[1
]}

Laaris, A. ^{[1
]}

Whitters, M. ^{[3
]}

Nagelin, A. M. ^{[4
]}

O'Hara, R. M., Jr. ^{[4
]}

Azimzadeh, A. M. ^{[1
]}

机构：

[1] Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA

[2] Hebei Med Univ, Hosp 3, Dept Cardiac Surg, Shijiazhuang, Hebei, Peoples R China

[3] Pfizer Res, Inflammat & Immunol, Cambridge, MA USA

[4] Wyeth Res, Inflammat Discovery Res, Cambridge, MA USA

来源：

AMERICAN JOURNAL OF TRANSPLANTATION | 2011年 / 11卷 / 08期

关键词：

CD28; CTLA-4; cardiac allograft vasculopathy; nonactivating; single-chain Fv; selective costimulatory; tolerance; T-CELL-ACTIVATION; MONOCLONAL-ANTIBODY; TRANSPLANTATION TOLERANCE; DENDRITIC CELLS; CYTOKINE STORM; CTLA-4; COSTIMULATION; INDUCTION; SURVIVAL; EXPRESSION;

D O I：

10.1111/j.1600-6143.2011.03624.x

中图分类号：

R61 [外科手术学];

学科分类号：

摘要：

Selective blockade of CD28 is a promising therapy to inhibit pathogenic alloimmunity. However, evaluation of this approach in transplantation has been very limited. Using a novel nonactivating single-chain Fv-based reagent (alpha 28scFv), we have investigated the role of CD28 and cytotoxic T lymphocyte antigen 4 (CTLA-4) in a murine cardiac transplant model. Blockade of CD28 for 2 weeks after engraftment promoted allograft survival, and significantly attenuated chronic rejection when combined with transient CD154-blockade or calcineurin inhibition. Graft acceptance was associated with decreased alloantibody production, increased proportion of early graft infiltration by regulatory T cells and increased expression of regulatory dendritic cell genes. Blockade of CTLA-4 during alpha 28scFv-based treatments led to prompt rejection in all animals and inhibited expression of forkhead box P3 (Foxp3), programmed death (PD)-1 and 2,3-indoleamine dioxygenase (IDO) in the graft. These results show that CD28 signaling during the first weeks after transplant is a pivotal mediator of pathogenic alloimmunity, and that selective CD28 blockade prolongs graft acceptance by at least two immunomodulatory mechanisms. Selective CD28 inhibition while sparing CTLA-4 is thus a promising approach to inhibit pathogenic alloimmunity.

引用

页码：1599 / 1609

页数：11

共 70 条

[61] Costimulation blockade with belatacept in renal transplantation [J].