Open Access, Peer-reviewed
pISSN 1598-2629 eISSN 2092-6685
Indexed in PubMed, Scopus and SCIE
    Immune Netw. 2010 Apr;10(2):46-54. English.
    Published online Apr 30, 2010.
    https://doi.org/10.4110/in.2010.10.2.46
    Copyright © 2010 The Korean Association of Immunologists
    Original Article

    Roles of Host Nonhematopoietic Cells in Autoimmunity and Donor Cell Engraftment in Graft-versus-host Disease

    Juyang Kim,1 Sohye Park,2 Hyun-A Kim,2 Daehee Jung,2 Hyun Ju Kim,2 Hye-Jeong Choi,3 Hong Rae Cho,1,4 and Byungsuk Kwon1,2
      • 1Biomedical Research Center, Ulsan University Hospital, School of Medicine, Ulsan, Korea.
      • 2School of Biological Sciences, University of Ulsan, Ulsan, Korea.
      • 3Department of Pathology, Ulsan University Hospital, School of Medicine, University of Ulsan, Ulsan, Korea.
      • 4Department of Surgery, Ulsan University Hospital, School of Medicine, University of Ulsan, Ulsan, Korea.
    • Corresponding author. Tel: 82-52-259-2860; Fax: 82-52-259-2740; Email: bkwon@mail.ulsan.ac.kr
    Received March 01, 2010; Revised March 25, 2010; Accepted March 31, 2010.

    This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Background

    Graft-versus-host disease (GVHD) is initiated when alloreactive donor T cells are primed by host APCs to undergo clonal expansion and maturation. Since there is a controversy regarding the role of nonhematopoietic cells in GVHD, we wanted to investigate the influence of MHC disparity on nonhematopoietic cells on the pathogenesis of GVHD in the MHC-haplomismatched C57BL/6 (H-2b) or DBA/2 (H-2d)→unirradiated (C57BL/6×DBA/2) F1(BDF1; H-2b/d) murine model of acute GVHD (aGVHD) or chronic GVHD (cGVHD).

    Methods

    We generated (BDF1→C57BL/6), (BDF1→DBA/2), and (BDF1→BDF1) chimeras and examined GVHD-related parameters and donor cell engraftment in those chimeras.

    Results

    Using this experimental system, we found that 1) severe aGVHD across MHC Ag barrier depends on the expression of nonhematopoietically rather than hematopoietically derived alloAgs for maximal GVHD manifestations; 2) host APCs were sufficient to break B cell tolerance to self molecules in cGVHD, whereas host APCs were insufficient to induce autoimmunity in aGVHD; 3) donor cell engraftment was greatly enhanced in the host with MHC-matched nonhematopoietic cells.

    Conclusion

    Taken together, our results provide an insight into how MHC disparity on GVHD target organs contribute to the pathogenesis of GVHD.

    Keywords
    Autoimmunity; Chimera; Graft-versus-host disease; Immune tolerance

    INTRODUCTION

    In the parent-into-F1 graft-versus host disease (GVHD) model, the genetic background of donor strains is critical in determining the outcome of GVHD (1, 2). For example, the infusion of donor T cells from the DBA/2 strain into an unirradiated (C57BL/6×DBA/2)F1 (BDF1) mouse induces chronic GVHD (cGVHD), whereas the infusion of T cells of the other parent, C57BL/6 (B6), induces acute GVHD (aGVHD) (3). CD4+ T cells of the DBA/2 strain activate and expand host B cells with an autoreactive potential, resulting in systemic lupus erythematosus (SLE)-like symptoms such as autoAb production and glomerulonephritis (4). In aGVHD, not only do donor CD8+ T cells eliminate host hematopoeietic cells, particularly host B cells, to induce massive engraftment of donor cells, but also donor CD8+ T cells attack solid organs together with immune cells regulated by donor CD4+ T cells, resulting in loss of body weight (1). It seems that donor CD8+ T cell anergy is a restriction factor for the development of cGVHD (5, 6). Even though donor CD4+ T cells have the ability to break host B cell tolerance in both cGVHD and aGVHD, donor CD8+ T cells have a different fate after transfer into the host; donor CD8+ T cells are rapidly eliminated from the host and the remaining cells fall into anergy in cGVHD (5, 6), whereas donor CD8+ T cells are differentiated into effector T cells that have the ability to delete host B cells including potential autoreactive B cells in aGVHD, thus depriving the host of the opportunity to produce autoAb (7-9).

    It is controversial whether cognate interactions between TCRs and MHC on nonhematopoietic target tissues are required for GVHD (10-13). In MHC-mismatched GVHD, TCRs can directly recognize recipient MHC (10-12). Teshima et al. (13) have shown that CD4-mediated GVHD, and to a lesser extent CD8-mediated GVHD do not require such direct interactions, suggesting that the direct allorecognition of donor T cells on host APCs is critical in GVHD. It is not known how donor B6 T cells induce GVHD in the B6→BDF1 aGVHD model. In this study, F1→parent chimeras were used to elucidate the involvement of alloAg expression by nonhematopoietic tissues in the B6→BDF1 aGVHD model. Our results indicate that aGVHD induced solely by alloreactive donor T cells depends on the expression of nonhematopoietically rather than hematopoietically derived alloAgs.

    MATERIALS AND METHODS

    Mice

    Female DBA/2 (H-2d) and BDF1 (H-2b/d) mice, 7~8 wk of age, were purchased from Orient (Seoul, Korea). All mice were maintained in pathogen-free conditions. These studies were approved by institutional animal care committee.

    Abs and reagents

    The following FITC-, PE-, PerCP- or biotin-conjugated mAbs to mouse proteins were purchased from BD Biosciences (San Diego, CA): CD4, CD8, B220, H-2Kb, H-2Kd, CD62L. HRP-conjugated rat anti-mouse IgG1 Abs also were purchased from BD Biosciences.

    Bone marrow (BM) reconstitution

    BM cells were collected by flushing femurs and tibias from BDF1 mice into MACS buffer (1×PBS containing 5 mM EDTA and 3% BSA). After erythrocyte lysis in hemolysis buffer (144 mM NH4Cl and 17 mM Tris-HCl, pH 7.2), BM cell were incubated with biotinylated anti-CD3 mAb for 20 min on ice, washed once, then incubated with streptavidin-conjugated microbeads (Miltenyi Biotech, Auburn, CA) for 20 min at 4℃. Cells were depleted of CD3+ cells using MACS buffer. Remaining CD3+ cells routinely comprised less than 1% of BM cells. Recipient BDF1 mice received 12 gray (Gy) irradiation from a cesium irradiator and were reconstituted with 5×106 T-cell-depleted BM from BDF1 mice.

    Induction of GVHD

    GVHD was induced as described previously (14-16). In brief, single-cell suspensions in PBS were prepared from spleens and lymph nodes of normal B6 or DBA2 donors, filtered through a sterile mesh (BD Biosciences), and washed. After the erythrocytes were lysed in hemolysis buffer, the remaining cells were resuspended at 8×107 cells/0.2 ml in PBS. GVHD was induced by transfer of 8×107 of spleens/lymph node cells into the tail vein of unirradiated BDF1 recipient mice at 12 wk after BM transplantation.

    ELISA

    Mice were bled from the tail vein, and serum titers of anti-DNA IgG1 were assessed by ELISA. Plates (96-well) were incubated overnight at 4℃ with 100 µl salmon sperm DNA (Sigma-Aldrich, St. Lois, MO) at a concentration of 10 µg/ml. After blocking with 2% BSA, the plates were incubated with 100 µl serially diluted serum samples for 1 h at room temperature. They were washed three times with PBS containing 0.1% Tween 20, and HRP-conjugated anti-mouse IgG1 was added to each well and the plates were kept at room temperature for 1 h. They were washed again with the same solution and color was developed in 100 µl 3,5,3',5'-tetramethylbenzene substrate (Pierce, Rockford, IL) for 10~15 min and stopped by adding 100 µl of 1 N HCl. The plates were then read at 450 nm with a Wallac Vector 1420 Multilabel Counter (PerkinElmer, Waltham, MA). OD values at a 1/10 dilution of sera were presented.

    Flow cytometry

    The spleens of GVHD mice were harvested on the indicated days after parental cell transfer. After lysis of the erythrocytes, the splenocytes were preincubated in a blocking buffer (PBS containing 2.4G2 mAb/0.2% BSA/0.1% sodium azide), and then incubated with the relevant mAbs for 30 min at 4℃. Finally, they were washed twice with staining buffer (PBS containing 0.2% BSA/0.1% sodium azide) and analyzed by FACscan (BD Biosciences).

    Histopathology

    Formalin-fixed kidney, liver, and large intestine were embedded in paraffin, and 5 µm thick sections were stained with H&E and evaluated by light microscopy. Slides for liver and large intestine were coded and further examined in a blinded fashion by one individual (H.J.C.), using a semiquantitative system for abnormalities known to be associated with aGVHD (17, 18). In brief, samples of liver tissue was performed by scoring 14 pathologic features, including inflammatory infiltrates in bile ducts and portal tracts, vascular endothelialitis, and hepatocellular damage as previously reported. A severity scale from one to four was used where 0=normal, 0.5=rare scattered, 1=minimal or focal, 2=mild and more diffuse, 3=moderate damage, and 4=severe damage. Scores for each individual feature were added to yield a composite score of liver pathology. Colon abnormalities were assessed by examining crypt regeneration, surface coloncytes, colonocyte vacuolization, surface colonocyte attenuation, crypt cell apoptosis, outright crypt destruction, and lamina propria lymphocytic infiltrate. The scoring system denoted 0 as normal, 0.5 as focal and rare, 1.0 as focal and mild, 2.0 as diffuse and mild, 3.0 as diffuse and moderate, and 4.0 as diffuse and severe. Scores were added to provide a total score for each specimen. Only after scoring was performed were codes broken and data compiled.

    Statistical analysis

    The Student's t test was used to determine the statistical significance of differences between experimental groups. Error bars represent SD of the mean. Log-rank Mantel-Cox test was used for survival curves.

    RESULTS

    The parent-into-unirradiated GVHD model is unique among GVHD models in that the development of GVHD is initiated only by alloreactivity without inflammation induced by preconditioning. This property provides a less complication in interpreting experimental data and finds its usefulness in an experimental tool to dissect a variety of issues related to immune tolerance to alloAgs. In this study, we wanted to investigate the roles of nonhematopoietic cells in GVHD in the MHC-haplomismatched B6 or DBA/2→unirradiated BDF1 murine model of aGVHD or cGVHD. We created (BDF1→B6), (BDF1→DBA/2), or (BDF1→BDF1) chimeras. In this experiment system, allogeneic host APCs could stimulate donor T cells, regardless of MHC mismatch in nonhematopoietic cells. PBMCs were >90% donor-derived in BDF1→B6 or DBA/2 mice by 8 wk after BM transfer (Fig. 1). We induced aGVHD in three sets of chimeras by transferring B6 spleen/lymph node cells. BDF1→DBA/2 chimeras had most severe aGVHD as measured by loss of body weight and histologic analysis of aGVHD target organs (Fig. 2). Except for earlier death in a small portion of mice, BDF1→B6 chimeras barely showed clinical and pathologic symptoms of aGVHD. The earlier death could be due to a large quantity of cytokines produced when B6 donor T cells killed host BDF1 hematopoietic cells (also see Fig. 2; Ref 13). BDF1→BDF1 control mice had milder aGVHD than BDF1→DBA/2 chimeras but more severe hepatic GVHD than BDF1→B6 chimeras. Taken together, our results indicate that severe aGVHD mediated by donor T cells depends on the expression of alloAgs in nonhematopoietic cells. A similar conclusion has been reached in CD8+ T cellor CD4+ T cell-mediated aGVGD across minor histocompatibility Ag (miHA) barrier (19, 20).

    Figure 1
    Confirmation of BM reconstitution. B6, DBA/2 and BDF1 mice received 12 Gy irradiation and were reconstituted with 5×106 T cell-depleted BDF1 BM cells. PBMCs were analyzed by flow cytometry at days 45 and 55 after cell transfer. Percent of donor cells were counted by staining PBMCs with anti-H-2Kb or H-2Kd mAbs (n=10~20 per group).

    Figure 2
    MHC disparity on nonhematopoietic cells exacerbates aGVHD. Eighty-four days after BM reconstitution, aGVHD was induced by transferring 8×107 B6 spleen/lymph node cells into three sets of mice (n=20 per group). (A) Loss of body weight. (B) Percent of survival. (C) Pathological scores for livers and colons. Organs were harvested at day 54 after disease induction (n=5~8 per group). †p<0.001, **p<0.01 and *p<0.05 between the indicated groups.

    In our experimental system, TCRs of donor B6 T cells could recognize intact BDF1 MHC on host hematopoietic cells. Alloreactive donor T cells generated from these interactions could remove host hematopoietic cells and make a niche for donor hematopoietic stem cells. As shown in Fig. 3, MHC disparity on nonhematopoietic cells had a reverse correlation with donor cell engraftment. Even though aGVHD was not evident in BDF1→B6 chimeras, more than 90% of splenocytes were of donor origin. In contrast, despite of severe aGVHD, DBF1→DBA/2 chimeras had the least extent of donor cell engraftment among the three sets of chimeras. Our data indicate that MHC disparity on nonhematopoietic cells is a greater hurdle to donor cell engraftment.

    Figure 3
    MHC match on nonhematopoietic cells increases donor cell engraftment in aGVHD. Eighty-four days after BM reconstitution, aGVHD was induced by transferring 8×107 B6 spleen/lymph node cells into three sets of mice (n=20 per group). Splenocytes were harvested at day 54 after disease induction and stained with anti-H-2Kd plus anti-CD4, anti-CD8 or B220. (A) Percent of total donor cells. (B) Percent of donor B cells. (C) Percent of donor CD4+ T cells. (D) Percent of donor CD8+ T cells (n=5~8 per group). †p<0.001, **p<0.01 and *p<0.05 between the indicated groups.

    It is thought that alloreactive donor T cells exhibit an activation status in MHC-mismatched GVHD, because they receive sustained allostimulation. Consistent with this hypothesis, a greater number of activated CD4+ T cells and CD8+ T cells (CD62Llow) were contained in the spleen of BDF1→DBA/2 chimeras and positive controls (BDF1→BDF1 mice), compared with BDF1→B6 mice (Fig. 4). Therefore, our result suggests that alloreactive T cells in BDF1→B6 chimeras may remain quiescent after allogenic host hemtopoietic cells are removed.

    Figure 4
    MHC match on nonhematopoietic cells decreases activation of donor T cells in aGVHD. Eighty-four days after BM reconstitution, aGVHD was induced by transferring 8×107 B6 spleen/lymph node cells into three sets of mice (n=20 per group). Splenocytes were harvested at day 54 after disease induction and stained with anti-H-2Kd plus anti-CD62L and anti-CD4 or anti-CD8. (A) Percent of donor CD4+CD62Llow T cells. (B) Percent of donor CD8+CD62Llow T cells (n=8 per group). †p<0.001, **p<0.01 and *p<0.05 between the indication groups.

    The DBA/2→BDF1 cGVHD model has been extensively utilized to study how alloimmunity breaks B-cell tolerance to self molecules (21). Using this model, we wanted to examine the effect of MHC disparity on nonhematopoietic cells on autoimmunity and donor cell engraftment. cGVHD was induced by transferring DBA/2 spleen/lymph node cells into BDF1→B6, BDF1→DBA/2, and BDF1→BDF1 chimeras. As shown in Fig. 5A, DBA/2 donor T cells were equally potent in inducing production of IgG1 anti-DNA autoAb in all of the three sets of chimeras, suggesting that MHC disparity on hematopoietic cells are sufficient for but MHC disparity on nonhematopoietic cells are not involved in the development of cGVHD. Furthermore, it seems that mortality due to cGVHD was not influenced by MHC disparity on nonhematoietic cells: there was no difference in the rate of mortality between BDF1→DBA/2 and BDF1→B6 chimeras (Fig. 5B). Histopathological analysis showed that the kidney of either BDF1→DBA/2 or BDF1→B6 chimeras had severe glomerulonephritis (Fig. 5C). Nontherless, engraftment of donor lymphocytes, including CD4+ T cells, CD8+ T cells, and B cells, was significantly higher in BDF1→DBA/2 than in BDF1→B6 chimeras, although the two groups had no difference in the percent of total donor cell engraftment (Fig. 6). Levels of donor lymphocyte engraftment were positively correlated with the extent of donor CD8+ T cell activation (Fig. 7). These results suggest that MHC match on nonhematopoietic cells is critical in donor cell engraftment, as shown in the B6→BDF1 aGVHD model.

    Figure 5
    MHC disparity on nonhematopoietic cells does not affect the development of cGVHD. B6, DBA/2 and BDF1 mice received 12 Gy irradiation and were reconstituted with 5×106 T cell-depleted BDF1 BM cells. Eighty-four days after BM reconstitution, cGVHD was induced by transferring 8×107 DBA/2 spleen/lymph node cells into three sets of mice (n=10 per group). (A) Serum samples were collected every 2 wk and assayed in duplicate by ELISA for IgG1 anti-DNA autoAb. The OD of duplicate samples for each mouse was measured at 450 nm, using serially diluted serum samples. (B) Percent of survival (n=10 per group). (C) Histology of kidneys harvested at day 54 after disease induction. Representative kidney sections are shown for H&E staining. *p<0.05 between the indicated groups.

    Figure 6
    MHC match on nonhematopoietic cells increases donor lymphocyte engraftment in cGVHD. Eighty-four days after BM reconstitution, cGVHD was induced by transferring 5×106 DBA/2 spleen/lymph node cells into three sets of mice (n=20 per group). Splenocytes were harvested at day 54 after disease induction and stained with anti-H-2Kb plus anti-CD4, anti-CD8 or B220. (A) Percent of total donor cells. (B) Percent of donor B cells. (C) Percent of donor CD4+ T cells. (D) Percent of donor CD8+ T cells (n=5~8 per group). **p<0.01 and *p<0.05 between the indicated groups.

    Figure 7
    Donor lymphocyte engraftment correlates with donor CD8+ T cell activation in cGVHD. Eighty-four days after BM reconstitution, aGVHD was induced by transferring 5×106 DBA/2 spleen/lymph node cells into three sets of mice (n=10 per group). Splenocytes were harvested at day 54 after disease induction and stained with anti-H-2Kb plus anti-CD62L and anti-CD4 or anti-CD8. (A) Percent of donor CD4+ CD62Llow T cells. (B) Percent of donor CD8+CD62Llow T cells (n=8 per group). *p<0.05 between the indicated groups.

    DISCUSSION

    In the B6→BDF1 aGVHD model, theoretically, MHC-haplomismatched host APCs can not only stimulate donor T cells through interactions between allo-MHC and TCRs but also present processed alloAgs or self-Ags to donor T cells in the context of self-MHC. Our results suggest that, even though GVHD is initiated by donor T cells after receiving allostimulation by host APCs, through the direct alloreactive pathway (22), presentation of nonhematopoietically derived alloAgs by donor APCs is a prerequisite for the propagation of the disease. It seems that (BDF1→B6) chimeras experience transient cachexia (which sometimes results in mortality) with reduced target-tissue injury over time, reflecting an early, limited graft-versus-host response. This interpretation is consistent with results obtained from various MHC-matched ormismatched aGVHD models (23-27).

    It is still controversial whether the expression of nonhematopoietically derived alloAgs is required for CD4-mediated aGVHD. Two sharp contrast results have been reported (13, 20). Teshima et al. (13) demonstrated in the MHC-disparate bm12→[B6→B6.MHC II-/-] BM chimera model that alloAg expression by the hematopoietic compartment alone was sufficient to obtain lethal GVHD, whereas Jones et al. (20) demonstrated significantly diminished B6 CD4+ T cell-mediated GVHD development when recipient BALB.B mHAs were exclusively derived from cells of the hematopoietic compartment. This discrepancy may be due to differences in the allogeneic T cell response directed across MHC versus mHA barriers, most notably the involvement of a much higher alloreactive CD4+ T cell precursor frequency in the former situation (28). In bm12→B6 (20) and similar models (18, 29-32), such a vigorous T cell response can rapidly generate high levels of proinflammatory cytokines responsible for initiating acute tissue damage in the early post-hematopoietic stem cell transplantation period. However, our results suggest that alloreactive T cells generated by the exposure to allogeneic host APCs are insufficient to drive fully developed GVHD in the absence of preconditioning. Therefore, proinflammatory cytokines produced as a result of preconditioning such as total body irradiation play a critical role in the induction of GVHD, presumably in synergy with a donor T cell response or/and by helping the broadening of the pool of alloreactive donor T cells (33-35). In either case, the data suggest that alloreactive donor T cells generated from either the direct pathway (by allogeneic host APCs) or the indirect pathway (nonhematopoietically derived alloAgs are presented by host or donor APCs) mediate GVHD with great help of proinflammatory cytokines triggered by preconditioning.

    It is well known that GVHD, in particular, cGVHD, has clinical manifestations of autoimmune disorders (36-38). Our observations showing that BDF1→B6 chimeras did not display aGVHD after transfer of B6 T cells suggest that allogeneic host APCs is insufficient to break self-tolerance. Since GVHD-induced autoreactivity is donor APC-dependent in irradiated recipient mice (39), and BDF1 APCs can present self-Ags to donor B6 T cells in BDF1→B6 chimeras, proinflammatory cytokines produced as a result of preconditioning may facilitate autoimmunity by donor T cells. In such irradiated models, autoimmunity is evolved as aGVHD is progressing (24). In our cGVHD model, alloreactive donor T cells (CD4+ T cells) rapidly broke B cell tolerance regardless of MHC match on nonhematopoietic cells. Therefore, a certain genetic combination of MHC disparity between donors and recipients may be a risk factor for SLE-like cGVHD, especially in patients with transient or chronic states of mixed chimerism. However, clinical correlates of these observations should be established.

    In the B6→BDF1 aGVHD model, alloreactive donor CD8+ T cells kill host hematopoietic cells for donor cell engraftment. Surprisingly, donor cell engraftment is not positively correlated with the severity of GVHD. This observation suggests that donor-recipient genetic combinations may exist where donor T cells do not induce GVHD with intact donor cell engraftment and thus intact graft-versus-leukemia effects. It will be important to search for a genetic factor that governs donor cell engraftment.

    Notes

    The author have no financial conflict of interest.

    ACKNOWLEDGEMENTS

    This work was supported by grants of the National R&D Program for Cancer Control (0820240), the Korean Health Technology R&D Program, Ministry for Health and Welfare (A080652 and A090692), and the Korean Research Foundation (KRF-2007-532-E00010).

    References

      1. Murphy WJ. Revisiting graft-versus-host disease models of autoimmunity: new insights in immune regulatory processes. J Clin Invest 2000;106:745–747.
      1. Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 2007;25:139–170.
      1. Via CS, Sharrow SO, Shearer GM. Role of cytotoxic T lymphocytes in the prevention of lupus-like disease disease occurring in a murine model of graft-vs-host disease. J Immunol 1987;139:1840–1849.
      1. Rus V, Svetic A, Nguyen P, Gause WC, Via CS. Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murine graft-versus-host disease. J Immunol 1995;155:2396–2406.
      1. Kim J, Choi WS, Kang H, Kim HJ, Suh J-H, Sakguchi S, Kwon B. Conversion of alloantigen-specific CD8+ T cell anergy to CD8+ T cell priming through in vivo ligation of glucocorticoid-induced TNF receptor. J Immunol 2006;176:5223–5231.
      1. Kim J, Park K, Kim HJ, Kim J, Kim H-A, Jung D, Kim HJ, Choi H-J, Choi S-K, Suh K, Cho HR, Kwon B. Breaking of CD8+ T cell tolerance through in vivo ligation of CD40 results in inhibition of chronic graft-versus-host disease and complete donor cell engraftment. J Immunol 2008;181:7380–7389.
      1. Via CS, Finkelman FD. Critical role of interleukin-2 in the development of acute graftversus-host disease. Int Immunol 1993;5:565–572.
      1. Shustov A, Luzina I, Nguyen P, Papadimitriou JP, Handwerger B, Elkon KB, Via CS. Role of perforin in controlling B-cell hyperactivity and humoral autoimmunity. J Clin Invest 2000;106:R39–R47.
      1. Via CS, Shustov A, Rus V, Lang T, Nguyen P, Finkelman FD. In vivo neutralization of TNF-α promotes humoral autoimmunity by preventing the induction of CTL. J Immunol 2001;167:6821–6826.
      1. Aosai F, Ohlen C, Ljunggren HG, Höqlund P, Franksson L, Ploegh H, Towsend A, Kärre K, Stauss HJ. Different types of allospecific CTL clones identified by their ability to recognize peptide loading-defective target cells. Eur J Immunol 1991;21:2767–2774.
      1. Man S, Saler RD, Engelhard VH. Role of endogenous peptide in human alloreactive cytotoxic T cell responses. Int Immunol 1992;4:367–375.
      1. Crumpacker DB, Alexander J, Cresswell P, Engelhard VH. Role of endogenous peptides in murine allogeneic cytotoxic T cell responses assessed using transfectants of the antigen-processing mutant 174xCEM.T2. J Immunol 1992;148:3004–3011.
      1. Teshima T, Ordemann R, Reddy P, Gagins S, Liu C, Cooke KR, Ferrara JL. Acute graft-vs-host disease does not required alloantigen expression on host epithelium. Nat Med 2002;8:575–581.
      1. Kim J, Choi WS, La S, Suh J-H, Kim B-S, Cho HR, Kwon BS, Kwon B. Stimulation with 4-1BB inhibits chronic graft-versus-host disease by inducing activation-induced cell death of donor CD4+ T cells. Blood 2005;105:2206–2213.
      1. Kim J, Choi WS, Kim HJ, Kwon B. Prevention of chronic graft-versus-host disease by stimulation with glucocorticoid-induced TNF receptor. Exp Mol Med 2006;38:94–99.
      1. Kim J, Kim HJ, Choi WS, Cho HR, Kwon B. Maintenance of CD8+ T-cell anergy by CD4+CD25+ regulatory T cells. Exp Mol Med 2006;38:494–501.
      1. Cooke KR, Krenger W, Martin TR, Kobzik L, Brewer J, Simmons R, Crawford JM, van den Brink MR, Ferra JL. Host reactive donor T cells are associated with lung injury after experimental allogeneic bone marrow transplantation. Blood 1998;92:2571–2580.
      1. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pal L, Ferrara JL. Total body irradiation effects on acute graft versus host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 1997;90:3204–3213.
      1. Korngold R, Sprent J. Features of T cells causing H-2-restricted lethal graft-vs-host disease across minor histocompatibility barriers. J Exp Med 1982;155:872–883.
      1. Jones SC, Murphy GF, Friedman TM, Korngold R. Importance of donor histocompatibility antigen expression by nonhematopoietic tissues in a CD4+ T cell mediated graft-versus-host disease. J Clin Invest 2003;112:1880–1886.
      1. Chu Y-W, Gress RE. Murine models of chronic graft-versus-host disease: insights and unresolved issues. Biol Blood Marrow Transplant 2008;14:365–378.
      1. Horowitz JB, Kaye J, Katz ME, Janeway CA Jr. Ability of fixed B-lymphoma cells to present foreign protein antigen graftments and allogeneic MHC molecules to a cloned helper-T cell line. Cell Immunol 1987;109:429–436.
      1. Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME, Liu J, Shlomchik MJ, Emerson SG. Prevention of graft versus host disease by inactivation of host antigen presenting cells. Science 1999;285:412–415.
      1. Zhang Y, Hexner E, Frank D, Emerson SG. CD4+ T cells de novo from donor hemopoietic stem cells mediate the evolution from acute to chronic graft-versus-host disease. J Immunol 2007;179:3305–3314.
      1. Benichou G, Takizawa PA, Olson CA, McMillian M, Secarz EE. Donor major histocompatibility complex (MHC) peptides are presented by recipient MHC molecules during graft rejection. J Exp Med 1992;175:305–308.
      1. Liu Z, Braunstein NS, Suciu-Foca N. T cell recognition of allopeptides in context of syngeneic MHC. J Immunol 1992;148:35–40.
      1. Matte CC, Liu J, Anderson BE, Athanasiadis I, Jain D, McNiff J, Shlomchik WD. Donor APCs are required for maximal GVHD but not for GVL. Nat Med 2004;10:987–992.
      1. Song HK, Noirchashm H, Lieu YK, Rostani S, Greeley SA, Barker CF, Naji A. Cutting edge: alloimmune responses against major and minor histocompatibility antigens: distinct division kinetics and requirement for CD28 costimulation. J Immunol 1999;162:2467–2471.
      1. Cooke KR, Hill GR, Crawford JM, Bungard D, Brinson YS, Delmonte J Jr, Ferrara JL. Tumor necrosis factor-alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J Clin Invest 1998;102:1882–1891.
      1. Krijianouski OI, Hill GR, Cooke KR, Teshima T, Crawford JM, Brinson YS, Ferrara JL. Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versushost disease. Blood 1999;94:825–831.
      1. Reddy P, Teshima T, Kukuruga M, Ordemann R, Liu C, Lowler K, Ferrara JL. Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis. J Exp Med 2001;194:1433–1440.
      1. Brown GR, Lee E, Thiele DL. TNF-TNFR2 interactions are critical for the development of intestinal graft-versus-host disease in MHC class II disparate (C57BL/6J→C57BL/6J×bm12)F1 mice. J Immunol 2002;168:3065–3071.
      1. Gonzalez M, Quezada SA, Blazar BR, Panoskaltsis-Mortari A, Rudensky AY, Noelle RJ. The balance between donor T cell anergy and suppression versus lethal graft-versus-host disease is determined by host conditioning. J Immunol 2002;169:5581–5589.
      1. Kim J, Kim HJ, Park K, Kim J, Choi HJ, Yagita H, Nam SK, Cho HR, Kwon B. Costimulatory molecule-targeted immunotherapy of chronic graft-versus-host disease. Blood 2007;110:776–782.
      1. Kim W, Kim J, Jung D, Kim H, Choi HJ, Cho HR, Kwon B. Induction of lethal graft-versus-host disease by anti-CD137 monoclonal antibody in mice prone to chronic GVHD. Biol Blood Marrow Transplant 2009;15:306–314.
      1. Rouquette-Gally AM, Boyeldieu D, Gluckman E, Abuaf N, Combrisson A. Autoimmunity in 28 patients after allogeneic bone marrow transplantation: comparison with Sjogren syndrome and scleroderma. Br J Haematol 1987;66:45–47.
      1. Rouquette-Gally AM, Boyeldieu D, Prost AC, Gluckman E. Autoimmunity after allogeneic bone marrow transplantation. A study of 53 long-term-surviving patients. Transplantation 1988;46:238–240.
      1. Sherer Y, Shoenfeld Y. Autoimmune disease and autoimmunity post-bone marrow transplantation. Bone Marrow Transplant 1998;22:873–881.
      1. Tivol E, Komorowski R, Drobyski WR. Emergent autoimmuity in graft-versus-host disease. Blood 2005;105:4885–4891.
    Cited by
    Crossref 1
    Google Scholar 
    PubMed Central 1
    MeSH Terms
    Autoimmunity
    Chimera
    Graft vs Host Disease
    Humans
    Immune Tolerance
    T-Lymphocytes
    Tissue Donors
    Metrics
    Share
    Links to
    Figures
    slide
    slide
    slide
    slide
    slide
    slide
    slide

    1 / 7

    PERMALINK