Graft-versus-host reactions: clues to the etiopathology of a spectrum of immunological diseases

Gleichmann, Ernst; Pals, Steven T.; Rolink, A G; Radaszkiewicz, T; Gleichmann, Helga

doi:10.1016/0167-5699(84)90126-9

Cited by 338 publications

(176 citation statements)

References 54 publications

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“…Thus the changes brought about by chronic GVHD, in the various cells capable of functioning as APC, can not only cause pathological clonal loss of T cells activated by a foreign antigen, but also induce autoimmunity against self antigens normally ignored. This is precisely supported by the experimental and clinical observations in chronic GVHD [1,2,4]. …”

Section: Discussionsupporting

confidence: 62%

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Antigen-presenting cells (APC) of mice with chronic graft-versus-host disease (GVHD) cause excessive activation-induced death of T helper cells

Haridas

Kamat

1997

Clinical and Experimental Immunology

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SUMMARYBoth experimental and clinical forms of chronic GVHD have unique immunological features. The affected animals/individuals suffer from autoimmune disorders such as systemic lupus erythematosus (SLE), and yet they are unable to mount a self MHC-restricted T cell response to foreign antigens. Pathogenesis of the latter phenomenon was investigated in an experimental model of chronic GVHD. Chronic GVHD was induced in 8-10-week-old (B6 × C3H)F 1 mice by tail vein injection of 5 × 10 7 spleen cells of C3H parental strain. The recipients, when tested 3 months later, were unable to mount a T helper (Th) cell response to a randomly selected immunogen, a vaccine of 10 8 killed Mycobacterium vaccae. The animals showed evidence of generalized lymphoid hyperplasia, as indicated by GVH index >1 . 34, and also revealed autoantibodies against erythrocytes and dsDNA, indicating establishment of chronic GVHD. However, mice with chronic GVHD of only 3 weeks duration were able to mount the Th cell response to M. vaccae. Three consecutive immunizations of these mice at 1-week intervals, with the same immunogen, resulted in the mice becoming non-responsive to the antigen. All the three responses tested, namely the DTH, lymphoproliferation and the antibody responses, were adversely affected. The non-responsiveness induced was antigen-specific. Mice receiving two immunizations with M. vaccae responded normally to Salmonella enteritidis. Pulse treatment with cyclosporin A 0 . 5 mg/mouse by the i.p. route, on days 0, 1, 2, 3 and 4 at the time of immunization with M. vaccae on day 1, prevented emergence of non-responsiveness. Based on this evidence, it was concluded that repeated activation of T cells of mice with chronic GVHD induces non-responsiveness. Extent of clonal loss due to activationinduced cell death (AICD) caused by i.p. injection with a superantigen Staphylococcal enterotoxin B (SEB) was investigated in F 1 mice with chronic GVHD. I.p. injection of 25 mg/mouse of SEB induced loss of SEB responding clones in both normal F 1 mice and those having chronic GVHD; however, the extent of loss was much greater in the latter. In vitro antigen-specific proliferation of primed splenic T cells of normal F 1 mice was observed to be quite poor when antigen was presented by APC of mice with chronic GVHD of 3 weeks duration. Proliferation profiles of T cells of normal F 1 mice, in response to stimulation with concanavalin A (Con A) or SEB, were studied, using as APC irradiated spleen cells of normal F 1 mice or of F 1 mice with chronic GVHD of 3 weeks duration. With Con A and APC of normal F 1 mice, peak proliferation was observed at 48 h, which remained at the same level up to 72 h and declined thereafter, possibly due to AICD. With SEB and the normal APC, proliferation progressively peaked at 72 h and declined thereafter. With APC of mice with chronic GVHD, the 48 h proliferative responses of both Con A and SEB were comparable to those caused by APC of normal F 1 mice; however, thereafter the responses declined steeply, suggesting gr...

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Section: Discussionsupporting

confidence: 62%

“…GVH index ¼ spleen weight=body weight of each test F 1 mean (spleen weight/body weight) of normal F 1 The above ratio, when >1 . 34, was considered as an indicator of successful induction of chronic GVHD.…”

Section: Assay Of Gvh Indexmentioning

confidence: 99%

Antigen-presenting cells (APC) of mice with chronic graft-versus-host disease (GVHD) cause excessive activation-induced death of T helper cells

Haridas

Kamat

1997

Clinical and Experimental Immunology

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“…Acute GVHD is induced by the transfer of both CD4 ϩ and CD8 ϩ donor T cells and is characterized by near-complete elimination of host B cells by donor antihost CTL at 2 wk after transfer. In contrast, chronic GVHD is induced by the transfer of donor CD4 ϩ T cells only and is characterized by donor CD4 ϩ T cell-driven B cell hyperactivity, elevated serum anti-ssDNA Ab by 2 wk, and lupus-like renal disease at Ͼ2 mo (32,42). Previous work in both mice and humans demonstrating that TCR-mediated T cell activation induces TRAIL up-regulation (43,44) suggests that donor T cell TRAIL expression may contribute to the induction of either form of GVHD.…”

Section: T Cell Trail Up-regulation Is Characteristic Of Acute Gvhd mentioning

confidence: 99%

T Cell TRAIL Promotes Murine Lupus by Sustaining Effector CD4 Th Cell Numbers and by Inhibiting CD8 CTL Activity

Rus

Nguyen

Puliaev

et al. 2007

The Journal of Immunology

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T cells play an essential role in driving humoral autoimmunity in lupus. Molecules such as TRAIL exhibit strong T cell modulatory effects and are up-regulated in lupus, raising the possibility that they may influence disease severity. To address this possibility, we examined the role of TRAIL expression on pathogenic T cells in an induced model of murine lupus, the parent-into-F1 (P→F1) model of chronic graft-vs-host disease (GVHD), using wild-type or TRAIL-deficient donor T cells. Results were compared with mice undergoing suppressive acute GVHD. Although chronic GVHD mice exhibited less donor T cell TRAIL up-regulation and IFN-α-inducible gene expression than acute GVHD mice, donor CD4+ T cell TRAIL expression in chronic GVHD was essential for sustaining effector CD4+ Th cell numbers, for sustaining help to B cells, and for more severe lupus-like renal disease development. Conversely, TRAIL expression on donor CD8+ T cells had a milder, but significant down-regulatory effect on CTL effector function, affecting the perforin/granzyme pathway and not the Fas ligand pathway. These results indicate that, in this model, T cell-expressed TRAIL exacerbates lupus by the following: 1) positively regulating CD4+ Th cell numbers, thereby sustaining T cell help for B cells, and 2) to a lesser degree by negatively regulating perforin-mediated CD8+ CTL killing that could potentially eliminate activated autoreactive B cells.

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“…In this model, mice exhibit a systemic autoimmune disorder characterized by splenomegaly, host B cell hyperactivation, autoantibody production, and immune complex deposition (10,11). In addition, mice with chronic GVHD exhibit increases in the number of total spleen cells, including host B cells, and in the levels of serum IgE, and of total IgG and IgG1 of anti-DNA Abs after chronic GVHD induction (12).…”

Section: Antagonist Of Secondary Lymphoid-tissue Chemokine (Ccr Liganmentioning

confidence: 99%

“…In addition, mice with chronic GVHD exhibit increases in the number of total spleen cells, including host B cells, and in the levels of serum IgE, and of total IgG and IgG1 of anti-DNA Abs after chronic GVHD induction (12). It has been postulated that alloreactive donor (DBA/2) CD4 ϩ T cells recognize MHC class II molecules on the B6D2F 1 host cells, and then provide help to host B cells for autoantibody production (10,13).…”

Section: Antagonist Of Secondary Lymphoid-tissue Chemokine (Ccr Liganmentioning

confidence: 99%

Antagonist of Secondary Lymphoid-Tissue Chemokine (CCR Ligand 21) Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

Sasaki

Hasegawa

Kohno

et al. 2003

The Journal of Immunology

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The use of receptor antagonists for chemokines is an alternative approach to blocking chemokine actions and has the potential to provide novel therapeutics. We determined the receptor antagonist properties of murine N-terminally truncated secondary lymphoid tissue chemokine (SLC)/6Ckine/CCR ligand 21 analogs and evaluated the preventive effects of SLC antagonists on chronic graft-vs-host disease (GVHD) in a murine model by blocking the homing of donor CCR7-expressing T cells into the recipient’s lymphoid organs. SLC analogs truncated >4 aa residues from the N terminus showed a loss of chemotaxis and Ca2+ influx of CCR7-expressing cells and also inhibited SLC-stimulated chemotaxis and SLC-induced Ca2+ influx completely. To determine whether SLC antagonist inhibits the development of chronic GVHD, chronic GVHD was induced by injecting DBA/2 spleen cells into (C57BL/6 × DBA/2) F1 mice. Total numbers of spleen cells and host B cells, serum levels of IgE, and of total IgG and IgG1 of anti-DNA Abs in SLC antagonist-treated GVHD mice were significantly lower than those in control PBS-treated GVHD mice. This was due to a reduction in the levels of activated donor CD4+ T cells and a decrease in IL-4 production, resulting in a reduction in the numbers of activated host B cells. Therefore, our results suggest that SLC antagonist has beneficial effects for the prevention of chronic GVHD.

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Graft-versus-host reactions: clues to the etiopathology of a spectrum of immunological diseases

Cited by 338 publications

References 54 publications

Antigen-presenting cells (APC) of mice with chronic graft-versus-host disease (GVHD) cause excessive activation-induced death of T helper cells

Antigen-presenting cells (APC) of mice with chronic graft-versus-host disease (GVHD) cause excessive activation-induced death of T helper cells

T Cell TRAIL Promotes Murine Lupus by Sustaining Effector CD4 Th Cell Numbers and by Inhibiting CD8 CTL Activity

Antagonist of Secondary Lymphoid-Tissue Chemokine (CCR Ligand 21) Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

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