Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic–derived antigen-presenting cells

Abstract

IntroductionAg presentation on radiosensitive host hematopoiesis-derived APCs to the alloreactive donor T cells is considered to be obligatory for the induction of acute GVHD. 1-9 However, under certain conditions, whether clinically relevant minor Ags can induce GVHD in the absence of functional radiosensitive host hematopoietic APCs is not known. [6][7][8]10 Clinical data from MHC-matched BMT show that male recipients from female donors (F3M) are at a greater risk of developing GVHD 9 and show H-Y-specific alloresponses. [11][12][13][14] These clinical data suggest a strong correlation between H-Y Ag disparity and GVHD. However, in the context of HLA-matched clinical F3M BMT, the donors are also likely to be mismatched with the recipients at multiple minor Ags. Therefore, whether H-Y disparity alone is sufficient for causing clinical acute GVHD is not known. The experimental evidence for the causative role of H-Y Ags in GVHD and mortality has not been reported. Furthermore, the relevance of donor T-cell alloreactivity against a single minor Ag and mechanisms of its presentation in causing GVHD are not known. [1][2][3][4][5] Although some studies have suggested that high doses of TCR transgenic (Tg) T cells can cause GVHD, its severity was limited and was in the context of MHC mismatch or against minor Ags with unknown clinical relevance. 15,16 With the use of both H-Y-specific Tg and non-Tg T cells in multiple well-established BM chimeras we demonstrate, in contrast to the existing notion, that presentation of clinically relevant minor H-Y Ag by host radiosensitive hematopoieticderived APCs is not obligatory for induction of acute GVHD. 3,[6][7][8]10,17 Our data further suggest that in the absence of radiosensitive host hematopoietic-derived APCs, when sufficient numbers of alloreactive donor T cells are infused, nonhematopoietic-derived cells such as endothelial and certain epithelial cells activate alloreactive T cells, might induce GVHD. Methods MiceMale and female C57BL/6 (B6, H-2 b , CD45.2 ϩ ), B6 Ly5.2 (H-2 b , CD45.1 ϩ ), and BALB/c (H-2 d ) mice were purchased from The Jackson 17 and MataHari (RAG-1 Ϫ background, CD8 ϩ Tg, H-2 b , CD45.2 ϩ , H-2D b -restricted) mice 18 were obtained from Taconic. All animals were cared for under regulations reviewed and approved by the University Committee on Use and Care of Animals of the University of Michigan, based on University Laboratory Animal Medicine guidelines. Generation of BM chimerasWe administered 1100 cGy total body irradiation ( 137 Cs source) to mice and then injected them intravenously with 5 ϫ 10 6 BM cells with 5 ϫ 10 6 whole spleen cells from donor mice on day Ϫ1. For generating MHC class I-deficient (␤2m-KO) BM chimeras, recipient mice were treated with 200 g of anti-NK1.1 mAb (PK136) on days Ϫ2 and Ϫ1. 6 The peripheral blood from sentinel mice were analyzed for donor chimerism at 3 months and found to show Ͼ 98% donor chimerism in all cell lineages. The CD11c ϩ cells in the splenocytes from these animals also showed Ͼ 95% donor chimerism. BMTBMT...

Risk factors and organ involvement of chronic GVHD in Japan

“…T cells transplanted from adult female donors can be activated by exposure to Y-chromosome-associated proteins and may cause chronic GVHD, but those from female U-CB units may be less activated against them. 31 Studies on the effect of the CMV Ab on chronic GVHD development have previously yielded controversial results. 2,32 In this study, we observed a significant impact of CMV seropositivity on the incidences of chronic GVHD and extensive chronic GVHD.…”

Siglec-G–CD24 axis controls the severity of graft-versus-host disease in mice

“…36,37 Recent data have indicated that both host hematopoietic or nonhematopoietic APCs, in the absence of one or another, can activate donor T cells and induce GVHD. 18,19,21 Furthermore, the elimination of specific hematopoietic APC subsets, such as DCs or macrophages, may aggravate GVHD, suggesting that these cells may play a role in controlling GVHD. 18,20,22,44 These observations, taken in light of our data, suggest that the negative regulatory pathways of professional APCs, DCs, or macrophages, might be critical for reducing GVHD severity following its induction by the activation of donor T cells by the DAMP/PAMP activated host APCs.…”

“…This is particularly critical in light of the recent observations, which demonstrate that the absence of any one subset of professional host-derived hematopoietic APCs, such as DCs or macrophages, contrary to the expectations of reducing donor T-cell responses, are either irrelevant, or actually enhance donor T-cell responses and accentuate GVHD severity. [18][19][20][21][22] These newer observations suggest that pathways that mitigate the hematopoietic APCs may be as critical for attenuating GVHD.…”

Siglec-G represses DAMP-mediated effects on T cells

“…FACS analyses were performed as previously described (38,39). Briefly, to analyze donor T cell expansion and activation markers, splenocytes from transplant-recipient mice were resuspended in FACS wash buffer (2% BSA in PBS) and stained with the following conjugated mAbs: PerCP-Cy5.5-conjugated mAbs against mouse CD4 (clone GK1.5) and CD8 (clone 53-6.7); PE-conjugated mAbs against mouse CD69 (clone H1.2F3), CD183 (CXCR3) (clone CXCR3-173), LPAM-1 (integrin α4β7) (clone DATK32), CD62L (clone MEL-14), and TIGIT (clone 1G9); APC-conjugated mAbs against mouse H-2K b (clone AF6-88.5), CD44 (clone IM7), PD-1 (clone 29F.1A12), and Lag3 .…”