Evidence That Large Granular Lymphocytes of Donor Origin Mediate Acute Graft-Versus-Host Disease

Ferrara, JL; Fj, Guillén; Pj, van Dijken; Marion, Ariënne M W van; Gf, Murphy; Sj, Burakoff

doi:10.1097/00007890-198901000-00012

Cited by 74 publications

(32 citation statements)

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“…This is in line with previous studies suggesting that LGL populations can be involved in graft-versus-host reactions, 34 can mediate a cytotoxic activity against neoplastic cells, 8 or can be associated with solid organ allograft rejection. 35,36 Besides their putative anti-tumoral activity, LGL expanded following allo-SCT in our series were also associated with adverse effects against normal hematopoietic progenitors as evidenced by the different episodes of cytopenia encountered by our patients.…”

Section: Discussionsupporting

confidence: 92%

Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis

et al. 2002

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Large granular lymphocyte (LGL) proliferation typically follows a chronic course during which major features are cytopenia and immune abnormalities. Elevated numbers of LGL were reported in a few cases following allogeneic stem cell transplantation (allo-SCT). In this report, we present a retrospective analysis of LGL cases that occurred following allo-SCT in a cohort of 201 consecutive patients transplanted over a period of 7 years. Six cases were identified and LGL expansion occurred more frequently following a reduced fludarabine and anti-T lymphocyte globulin-based preparative regimen (4 cases/49), than after a conventional myeloablative regimen (2 cases/152). Expansion of LGL was seen between 3 and 15 months following allo-SCT. Hematopoiesis, with mild to severe cytopenia, was a favored target for LGL. Autoimmune manifestations including polyarthritis and hypergammaglobulinemia were also observed. LGL proliferation was observed in the context of chronic antigenic stimulation associated with recurrent viral infections especially CMV. Moreover, five out of these six high risk patients achieved a long-term complete remission concomitant or following LGL expansion. These data suggest that LGL might be a subset of effector lymphocytes which may participate to the graft-versus-tumor effect.

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Section: Discussionsupporting

confidence: 92%

Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis

et al. 2002

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“…In contrast to T cells, a clear link has been established between murine SGVHD and innate immunity. Splenic NK activity has been shown to be enhanced following CsA treatment of syngeneic bone marrow (BM)-transplanted mice (17)(18)(19), and the in vivo depletion of NK cells inhibited development of the disease (16). Activated macrophages (dendritic cells) and their secreted products have also been shown to be critical in the disease process in that inhibition of IL-12, TNF-␣, and NO, after cessation of CsA therapy, prevented the development of SGVHD (16,20,21).…”

Section: S Yngeneic Graft-vs-host Disease (Sgvhd)mentioning

confidence: 99%

CD4+ T Cells Mediate Murine Syngeneic Graft-versus-Host Disease-Associated Colitis

Bryson

Zhang

Goes

et al. 2004

The Journal of Immunology

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Syngeneic graft-vs-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow, and treatment with a 21-day course of the immunosuppressive agent cyclosporin A (CsA). Following cessation of CsA, this inducible disease is characterized by weight loss, diarrhea, and development of inflammation in the colon and liver. Although nonspecific effector cells and Th1 cytokines have been shown to participate in disease induction, the role of T cells has not been fully elucidated. Initial studies demonstrated significant increases in CD4+ T cells, but not other T cell populations in the colons of diseased animals relative to transplant control animals. To demonstrate a functional linkage between increases in colonic CD4+ T cells and disease induction, in vivo T cell depletion studies were performed. Beginning on the day of bone marrow transplantation, groups of control and CsA-treated animals were treated with mAb against either CD4 or CD8 for 21 days. Treatment with anti-CD4, but not anti-CD8, eliminated clinical symptoms and colon pathology. Interestingly, neither anti-CD4 nor anti-CD8 therapy affected the development of liver pathology associated with SGVHD. These findings demonstrated that CD4+ T cells initiate development of the intestinal inflammation associated with murine SGVHD.

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“…USA 88 (1991) 10893 18), but the cells that we observed during GVHD did not express antigens that are characteristic of macrophages or dendritic Langerhans cells (measured by lack ofanti-Ia and F/480 staining; data not shown). We also analyzed these cells for markers of natural killer lineage because large granular lymphocytes have been implicated as effectors of GVHD in this murine model (7,8). CD4' lymphocytes in GVHD skin were uniformly NK1.1-, and thus not typical natural killer cells, although =40% were asialoganglioside GM1 positive (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…The skin is a major GVHD target organ, and during acute GVHD the epidermis is primarily affected. In a well-defined murine model (7,8), epidermal necrosis peaks early after transplant (week 3). These cells are Thy-1+ and CD2', are of donor origin, and bear no macrophage markers.…”

Section: Introductionmentioning

confidence: 99%

Lymphocytes with a CD4+ CD8- CD3- phenotype are effectors of experimental cutaneous graft-versus-host disease.

Sakamoto¹,

Michaelson²,

Jones³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Graft-versus-host disease (GVHD) is known to cause profound dysregulation of the immune system, although its effector mechanisms are poorly understood. We now describe an effector lymphocyte of unusual phenotype in the skin of mice with GVHD. This cell is of donor origin and expresses several T-cell surface proteins including Thy-i, CD2, and CD4 but does not express CD8, CD3, NK1.l, or macrophage antigens. Mononuclear cells of this phenotype are the predominant lymphocyte in the epidermis ofmice with GVHD 3 weeks after transplant but are not detected in transplanted mice without GVHD. Isolation and transfer of these lymphocytes into secondary recipients causes epidermal damage characteristic of GVHD. These data demonstrate that CD4+ CD8-CD3-lymphocytes are an important effector population that can be amplified outside the thymus and that can mediate target organ damage of GVHD.Graft-versus-host disease (GVHD) remains a major complication of allogeneic bone marrow transplantation. Mature T cells in the donor bone marrow initiate GVHD in immunocompromised or otherwise susceptible hosts (1-5). The afferent arm ofGVHD, including the subsets ofT cells required to initiate the reaction in response to various histocompatibility antigens, has been carefully studied (3-5). However, the constellation of target organs affected during clinical disease is unusual (skin, intestine, liver, immune system), and the nature of effector-target interactions is obscure (6).To understand these interactions, we have studied the lymphocytes that appear in the skin during GVHD. The skin is a major GVHD target organ, and during acute GVHD the epidermis is primarily affected. In a well-defined murine model (7,8), epidermal necrosis peaks early after transplant (week 3). These cells are Thy-1+ and CD2', are of donor origin, and bear no macrophage markers. Recently, a similar population of CD4' CD8-CD3-thymocytes was described in normal thymus, which expands during periods of rapid thymocyte proliferation, such as during fetal ontogeny and after bone marrow transplantation (9-11). In addition, the earliest T-lineage precursor cells in the thymus express CD4 prior to rearrangement of T-cell receptor genes (12). Our data show that CD4'

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Evidence That Large Granular Lymphocytes of Donor Origin Mediate Acute Graft-Versus-Host Disease

Cited by 74 publications

References 0 publications

Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis

Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis

CD4+ T Cells Mediate Murine Syngeneic Graft-versus-Host Disease-Associated Colitis

Lymphocytes with a CD4+ CD8- CD3- phenotype are effectors of experimental cutaneous graft-versus-host disease.

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