Wolf Dietlinde, Barreras Henry, Bader Cameron S, Copsel Sabrina, Lightbourn Casey O, Pfeiffer Brent J, Altman Norman H, Podack Eckhard R, Komanduri Krishna V, Levy Robert B
Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida.
Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.
Biol Blood Marrow Transplant. 2017 May;23(5):757-766. doi: 10.1016/j.bbmt.2017.02.013. Epub 2017 Feb 20.
Regulatory T cells (Tregs) are critical for self-tolerance. Although adoptive transfer of expanded Tregs limits graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT), ex vivo generation of large numbers of functional Tregs remains difficult. Here, we demonstrate that in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with IL-2, resulted in transient but massive Treg expansion in donor mice, which peaked within days and was nontoxic. Tregs increased in multiple compartments, including blood, lymph nodes, spleen, and colon (GVHD target tissue). Tregs did not expand in bone marrow, a critical site for graft-versus-malignancy responses. Adoptive transfer of in vivo-expanded Tregs in the setting of MHC-mismatched or MHC-matched allogeneic HSCT significantly ameliorated GVHD. Critically, transplantation of Treg-expanded donor cells facilitated transplant tolerance without GVHD, with complete sparing of graft-versus-malignancy. This approach may prove valuable as a therapeutic strategy promoting transplantation tolerance.
调节性T细胞（Tregs）对自身耐受至关重要。尽管过继转移扩增的Tregs可限制造血干细胞移植（HSCT）后的移植物抗宿主病（GVHD），但体外大量生成功能性Tregs仍然困难。在此，我们证明，使用TL1A-Ig融合蛋白以及白细胞介素-2在体内靶向肿瘤坏死因子超家族受体TNFRSF25，可导致供体小鼠体内Tregs短暂但大量扩增，在数天内达到峰值且无毒。Tregs在多个部位增加，包括血液、淋巴结、脾脏和结肠（GVHD靶组织）。Tregs在骨髓中未扩增，骨髓是移植物抗恶性肿瘤反应的关键部位。在MHC不匹配或MHC匹配的同种异体HSCT中过继转移体内扩增的Tregs可显著改善GVHD。至关重要的是，移植Treg扩增的供体细胞可促进移植耐受而无GVHD，且完全保留移植物抗恶性肿瘤作用。这种方法可能作为一种促进移植耐受的治疗策略被证明具有价值。
