Blazar B R, Taylor P A, Panoskaltsis-Mortari A, Sharpe A H, Vallera D A
Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis 55455, USA.
J Immunol. 1999 Jun 1;162(11):6368-77.
Blockade with B7 antagonists interferes with CD28:B7 and CTLA-4:B7 interactions, which may have opposing effects. We have examined the roles of CD28:B7 and CTLA-4:B7 on in vivo alloresponses. A critical role of B7:CD28 was demonstrated by markedly compromised expansion of CD28-deficient T cells and diminished graft-versus-host disease lethality of limited numbers of purified CD4+ or CD8+ T cells. When high numbers of T cells were infused, the requirement for CD28:B7 interaction was lessened. In lethally irradiated recipients, anti-CTLA-4 mAb enhanced in vivo donor T cell expansion, but did not affect, on a per cell basis, anti-host proliferative or CTL responses of donor T cells. Graft-versus-host lethality was accelerated by anti-CTLA-4 mAb infusion given early post-bone marrow transplantation (BMT), mostly in a CD28-dependent fashion. Donor T cells obtained from anti-CTLA-4 mAb-treated recipients were skewed toward a Th2 phenotype. Enhanced T cell expansion in mAb-treated recipients was strikingly advantageous in the graft-versus-leukemia effects of delayed donor lymphocyte infusion. In two different systems, anti-CTLA-4 mAb enhanced the rejection of allogeneic T cell-depleted marrow infused into sublethally irradiated recipients. We conclude that blockade of the selective CD28-B7 interactions early post-BMT, which preserve CTLA-4:B7 interactions, would be preferable to blocking both pathways. For later post-BMT, the selective blockade of CTLA-4:B7 interactions provides a potent and previously unidentified means for augmenting the GVL effect of delayed donor lymphocyte infusion.
用B7拮抗剂进行阻断会干扰CD28:B7和CTLA - 4:B7的相互作用，这可能会产生相反的效果。我们已经研究了CD28:B7和CTLA - 4:B7在体内同种异体反应中的作用。B7:CD28的关键作用通过CD28缺陷型T细胞的显著受损扩增以及有限数量的纯化CD4 +或CD8 + T细胞的移植物抗宿主病致死率降低得以证明。当输注大量T细胞时，对CD28:B7相互作用的需求就会减少。在接受致死性照射的受体中，抗CTLA - 4单克隆抗体增强了体内供体T细胞的扩增，但在单个细胞基础上，并不影响供体T细胞的抗宿主增殖或CTL反应。在骨髓移植（BMT）后早期给予抗CTLA - 4单克隆抗体输注会加速移植物抗宿主致死率，主要是以CD28依赖的方式。从抗CTLA - 4单克隆抗体处理的受体获得的供体T细胞倾向于Th2表型。在延迟供体淋巴细胞输注的移植物抗白血病效应中，单克隆抗体处理的受体中增强的T细胞扩增具有显著优势。在两个不同的系统中，抗CTLA - 4单克隆抗体增强了输注到亚致死性照射受体中的同种异体T细胞去除骨髓的排斥反应。我们得出结论，在BMT后早期阻断选择性CD28 - B7相互作用，同时保留CTLA - 4:B7相互作用，比阻断两条途径更可取。对于BMT后期，选择性阻断CTLA - 4:B7相互作用为增强延迟供体淋巴细胞输注的GVL效应提供了一种强大且前所未有的手段。
