Krenger W, Snyder K M, Byon J C, Falzarano G, Ferrara J L
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
J Immunol. 1995 Jul 15;155(2):585-93.
Acute graft-vs-host disease (GVHD) is thought to be mediated by alloreactive T cells with a type 1 cytokine phenotype. To prevent the development of acute GVHD, we have successfully polarized mature donor T cells toward a type 2 cytokine phenotype ex-vivo by incubating them with murine rIL-4 in a primary MLC. Polarized type 2 T cells were then transplanted with T cell-depleted bone marrow cells into irradiated recipients across either MHC class II (bm12-->C57BL/6) or class I (bm1-->C57BL/6) barriers, and the intensity of GVHD was measured by assessment of several in vitro and in vivo parameters. The injection of polarized type 2 T cells abrogated the mitogen-induced production of IFN-gamma by splenocytes from transplanted hosts on day 13 after bone marrow transplantation (BMT). Injection of polarized type 2 T cells failed to induce secretion of the effector phase cytokine TNF-alpha by splenocytes stimulated with LPS both in vitro and in vivo, and survival of transplanted mice after i.v. injection with LPS was significantly improved. Furthermore, cell-mixing experiments revealed that polarized type 2 T cells were able to inhibit type 1 cytokine responses induced by naive T cells after BMT. These data demonstrate that both polarized CD4+ and CD8+ type 2 alloreactive donor T cells can be generated in vitro from mature T cell populations. These cells function in vivo to inhibit type 1 T cell responses, and such inhibition attenuates the systemic morbidity of GVHD after BMT across both MHC class II or class I barriers in mice.
急性移植物抗宿主病（GVHD）被认为是由具有1型细胞因子表型的同种反应性T细胞介导的。为了预防急性GVHD的发生，我们通过在初次混合淋巴细胞培养（MLC）中用小鼠重组白细胞介素-4（rIL-4）孵育成熟供体T细胞，成功地在体外将其极化为2型细胞因子表型。然后将极化的2型T细胞与去除T细胞的骨髓细胞一起移植到经照射的受者体内，跨越MHC II类（bm12→C57BL/6）或I类（bm1→C57BL/6）屏障，并通过评估几个体外和体内参数来测量GVHD的强度。在骨髓移植（BMT）后第13天，注射极化的2型T细胞消除了移植宿主脾细胞由丝裂原诱导的γ干扰素产生。注射极化的2型T细胞在体外和体内均未能诱导经脂多糖（LPS）刺激的脾细胞分泌效应期细胞因子肿瘤坏死因子-α（TNF-α），静脉注射LPS后移植小鼠的存活率显著提高。此外，细胞混合实验表明，极化的2型T细胞能够抑制BMT后幼稚T细胞诱导的1型细胞因子反应。这些数据表明，极化的CD4+和CD8+ 2型同种反应性供体T细胞均可在体外由成熟T细胞群体产生。这些细胞在体内发挥作用以抑制1型T细胞反应，并且这种抑制作用减轻了小鼠跨越MHC II类或I类屏障进行BMT后GVHD的全身发病率。
