Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the role of perforin-mediated cytotoxic T lymphocyte (CTL) effector function in immune regulation, we studied a well-characterized mouse model of graft-versus-host disease (GVHD). Induction of acute GVHD using perforin-deficient donor T cells (pfp-->F1) initially resulted in features of acute GVHD, e.g., engraftment of both donor CD4(+) and CD8(+) T cells, upregulation of Fas and FasL, production of antihost CTL, and secretion of both Th1 and Th2 cytokines. Despite fully functional FasL activity, pfp donor cells failed to totally eliminate host B cells, and, by 4 weeks of disease, cytokine production in pfp-->F1 mice had polarized to a Th2 response. Pfp-->F1 mice eventually developed features of chronic GVHD, such as increased numbers of B cells, persistence of donor CD4 T cells, autoantibody production, and lupuslike renal disease. We conclude that in the setting of B- and T-cell activation, perforin plays an important immunoregulatory role in the prevention of humoral autoimmunity through the elimination of both autoreactive B cells and ag-specific T cells. Moreover, an ineffective initial CTL response can evolve into a persistent antibody-mediated response and, with it, the potential for sustained humoral autoimmunity.
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PMID:Role of perforin in controlling B-cell hyperactivity and humoral autoimmunity. 1099 84

Several bone marrow cells and lymphocyte subpopulations, known as "veto cells," were shown to induce transplantation tolerance across major histocompatibility antigens. Recently, it has been suggested that anti-third party CTLs depleted of alloreactivity are endowed with marked veto activity and therefore might potentially facilitate bone marrow allografting without graft versus host disease (GVHD). The veto mechanism is still obscure. While early studies emphasized the role of CD8-mediated apoptosis, more recent evidence indicates a role for Fas-FasL. In the present study we show, by using blocking anti-CD8 antibody, by generating CTLs from FasL or perforin mutated mice, and by gene transfer of FasL, that the veto activity of anti-third party CD8+ CTLs is dependent upon the simultaneous expression of both CD8 and FasL.
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PMID:Anti-third party CD8+ CTLs as potent veto cells: coexpression of CD8 and FasL is a prerequisite. 1107 Jan 69

Recent studies have demonstrated that granzymes A and B make an important contribution to the clearance of the orthopoxvirus ectromelia, and in graft versus host disease. To test whether granzymes are generally necessary for lymphocyte-mediated cytotoxicity in vivo, we assessed the cytotoxic capacity of granzyme A and/or B-deficient lymphocytes in several perforin-dependent settings. Splenocytes and allogeneic CTL of granzyme A and/or B-deficient mice were defective for induction of DNA fragmentation, but induced significant membrane damage and target cell death. These results correlated well with the behavior of granzyme A/B-deficient CTL and NK cells in three different perforin-dependent tumor models. In a classical assay of NK cell-mediated rejection, granzyme A and/or B-deficient mice inoculated with RMA-S cells were as susceptible to tumor as wild-type mice. Perforin-deficient mice were also considerably more susceptible to tumor initiation by methylcholanthrene than granzyme A and/or B-deficient mice. Furthermore, rejection of the K1735-melanoma expressing MHC class I and II molecules was mediated by adoptively transferred H-2b anti-k CTL from immunized granzyme A and/or B-deficient mice. In summary, these data suggest that granzymes A and B are not critical for most anti-tumor effector functions of NK cells and CTL that are perforin mediated.
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PMID:Granzyme A and B-deficient killer lymphocytes are defective in eliciting DNA fragmentation but retain potent in vivo anti-tumor capacity. 1116 36

In allogeneic bone marrow transplantation (BMT) donor T cells are primarily responsible for antihost activity, resulting in graft-versus-host disease (GVHD), and for antileukemia activity, resulting in the graft-versus-leukemia (GVL) effect. The relative contributions of the Fas ligand (FasL) and perforin cytotoxic pathways in GVHD and GVL activity were studied by using FasL-defective or perforin-deficient donor T cells in murine parent --> F1 models for allogeneic bone marrow transplantation. It was found that FasL-defective B6.gld donor T cells display diminished GVHD activity but have intact GVL activity. In contrast, perforin-deficient B6.pfp(-/-) donor T cells have intact GVHD activity but display diminished GVL activity. Splenic T cells from recipients of B6.gld or B6.pfp(-/-) T cells had identical proliferative and cytokine responses to host antigens; however, splenic T cells from recipients of B6.pfp(-/-) T cells had no cytolytic activity against leukemia cells in a cytotoxicity assay. In experiments with selected CD4(+) or CD8(+) donor T cells, the FasL pathway was important for GVHD activity by both CD4(+) and CD8(+) T cells, whereas the perforin pathway was required for CD8-mediated GVL activity. These data demonstrate in a murine model for allogeneic bone marrow transplantation that donor T cells mediate GVHD activity primarily through the FasL effector pathway and GVL activity through the perforin pathway. This suggests that donor T cells make differential use of cytolytic pathways and that the specific blockade of one cytotoxic pathway may be used to prevent GVHD without interfering with GVL activity.
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PMID:Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. 1131 85

T cells with natural killer cell phenotype and function (NKT cells) have been described in both human and murine tissues. In this study, culture conditions were developed that resulted in the expansion of CD8(+) NKT cells from bone marrow, thymus, and spleen by the timed addition of interferon-gamma (IFN-gamma), interleukin 2 (IL-2), and anti-CD3 monoclonal antibody. After 14 to 21 days in culture, dramatic expansion of CD3(+), CD8(+), alphabetaT-cell receptor(+) T cells resulted with approximately 20% to 50% of the cells also expressing the NK markers NK1.1 and DX5. The CD8(+) NKT cells demonstrated lytic activity against several tumor target cells with more than 90% lysis by day 14 to day 21 of culture. Cytotoxicity was observed against both syngeneic and allogeneic tumor cell targets with the greatest lytic activity by the cells expressing either NK1.1 or DX5. The expanded CD8(+) NKT cells produce T(H)1-type cytokines with high levels of IFN-gamma and tumor necrosis factor alpha. Expansion of the CD8(+) NKT cells was independent of CD1d. Ly49 molecules were expressed on only a minority of cells. A single injection of expanded CD8(+) NKT cells was capable of protecting syngeneic animals from an otherwise lethal dose of Bcl1 leukemia cells. Expanded CD8(+) NKT cells produced far less graft-versus-host disease (GVHD) than splenocytes across major histocompatibility barriers, even when 10 times the number of CD8(+) NKT cells as compared to splenocytes were injected. This reduction in GVHD was related to IFN-gamma production since cells expanded from IFN-gamma knock-out animals caused acute lethal GVHD, whereas cells expanded from animals defective in fas ligand, fas, IL-2, and perforin did not. These data indicate that CD8(+) NKT cells expanded in this fashion could be useful for preserving graft-versus-leukemia activity without causing GVHD.
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PMID:Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. 1134 13

Nonmyeloablative host conditioning regimens have been used in clinical allogeneic bone marrow and hematopoietic progenitor transplantation to effectively treat lymphohematopoietic tumors and reduce early toxicity. However, severe graft-versus-host disease (GVHD) remains a major problem. The goal of the current study was to determine whether specific subsets of cells in allogeneic bone marrow transplants can effectively treat the BCL(1) B-cell lymphoma in nonmyeloablated BALB/c mouse hosts given a single dose of sublethal (450 cGy) total body irradiation, without inducing severe GVHD. The experimental results show that high doses of whole bone marrow cells from major histocompatiblity complex (MHC)-mismatched donors eliminate both normal and malignant host-type lymphohematopoietic cells without causing injury to nonlymphohematopoietic host tissues. The CD8(+)T-cell antigen receptor-alphabeta+ (TCRalphabeta+) T cells within the marrow transplants mediated the killing of the tumor cells via both perforin- and FasL-dependent pathways. Cells present in marrow transplants from either CD8-/- or TCRalpha-/- donors failed to eliminate malignant and normal host lymphohematopoietic cells. Addition of small numbers of blood mononuclear cells to the marrow inoculum caused lethal GVHD. Thus, the resident allogeneic bone marrow CD8(+) TCRalphabeta+ T cells had the unique capacity to eliminate the host lymphohematopoietic cells without nonlymphohematopoietic tissue injury. (Blood. 2001;97:3458-3465)
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PMID:Allogeneic bone marrow cells that facilitate complete chimerism and eliminate tumor cells express both CD8 and T-cell antigen receptor-alphabeta. 1136 37

Experimental allogeneic bone marrow transplantation (BMT) models using cytotoxic single-deficient (perforin/granzyme or Fas ligand [FasL]) and cytotoxic double-deficient (cdd) CD4(+) donor T cells have previously demonstrated roles for both effector pathways in graft-versus-host disease (GVHD). In the present study, the role of CD4-mediated antihost cytotoxicity in a GVH response is further examined across a complete major histocompatibility complex class I/II mismatch. As predicted, a double cytotoxic deficiency resulted in a clear delay in GVH-associated weight loss, clinical changes, and mortality. Interestingly, analysis of donor T-cell presence in 5.5-Gy recipients soon after BMT demonstrated that the double cytotoxic deficiency resulted in a marked decrease in donor CD4 numbers. Transplantation of singularly perforin- or FasL-deficient donor CD4(+) T cells demonstrated that the absence of FasL was responsible for the markedly diminished CD4 number in recipient lymph nodes and spleens soon after BMT. However, increasing recipient total body irradiation conditioning (11.0 Gy) abrogated the decrease in FasL-defective B6-cdd and B6-gld CD4 numbers. Thus, the decrease was not a result of inherent CD4 defects, but was probably attributable to host resistance. Consistent with these observations, transplantation into 11.0-Gy recipients resulted in identical GVH lethality by equal numbers of B6 wild-type, B6-cdd, and B6-gld CD4(+) T-cell inoculum. In total, the findings indicate that aggressive host conditioning lessens the requirement for donor CD4(+) cytotoxic function in GVH responses soon after BMT. The present results thus support the notion of a role for cytotoxic effector function in donor CD4(+) T cells prior to GVH-induced tissue injury.
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PMID:Major histocompatibility complex-mismatched allogeneic bone marrow transplantation using perforin and/or Fas ligand double-defective CD4(+) donor T cells: involvement of cytotoxic function by donor lymphocytes prior to graft-versus-host disease pathogenesis. 1143 8

Cytotoxic lymphocytes largely comprise CD8(+) cytotoxic T cells and natural killer cells and form the major defense of higher organisms against virus-infected and transformed cells. A key function of cytotoxic lymphocytes is to detect and eliminate potentially harmful cells by inducing them to undergo apoptosis. This is achieved through two principal pathways, both of which require direct but transient contact between the killer cell and its target. The first, involving ligation of TNF receptor-like molecules such as Fas/CD95 by their cognate ligands, results in mobilization of conventional, programmed cell-death pathways centered on activation of pro-apoptotic caspases. This review concentrates on the second pathway, in which the toxic contents of secretory vesicles of the cytotoxic lymphocyte are secreted toward the target cell, and some toxins penetrate into the target cell cytoplasm and nucleus. In addition to invoking a powerful stimulus to caspase activation, this "granule-exocytosis mechanism" provides a variety of additional strategies for overcoming inhibitors of the caspase cascade that may be elaborated by viruses. The key molecular players in this process are the pore-forming protein perforin and a family of granule-bound serine proteases or granzymes. The molecular functions of perforin and granzymes are under intense investigation in many laboratories including our own, and recent advances will be discussed. In addition, this review discusses the evidence pointing to the importance of perforin and granzyme function in pathophysiological situations as diverse as infection with intracellular pathogens, graft versus host disease, susceptibility to transplantable and spontaneous malignancies, lymphoid homeostasis, and the tendency to auto-immune diseases.
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PMID:Unlocking the secrets of cytotoxic granule proteins. 1143 81

Umbilical cord blood (UCB) is now widely accepted as a source of stem cells in patients with malignant hematologic and genetic disorders. We have recently reported that in a series of 30 pediatric UCB transplant recipients comparable outcome to that anticipated with other unrelated stem cell sources. In our series, however, the probability of GVHD for grade III-IV was 9% and no UCB recipient developed chronic GVHD. The reason for the low incidence of GVHD after UCB transplantation is not fully understood. Because functional NK cells are among the first population of lymphocytes to be detected in UCB transplant recipients, 2 months post-transplant on average, we wanted to establish whether NK cells could be implicated in reducing the risk of GVHD. Here, we confirm that early NK cells detected in UCB transplant recipients activate the granzyme/perforin lytic pathway and, in addition, they can mediate Fas/Fas ligand (FasL) activity, a finding not previously reported. Both pathways develop simultaneously and are detectable months before the other lymphocytes, notably CD8 are fully functional. Our contention, therefore, is that the low GVHD observed in UCB recipients may be partially due to early NK cells.
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PMID:NK cells recover early and mediate cytotoxicity via perforin/granzyme and Fas/FasL pathways in umbilical cord blood recipients. 1147 1

A novel IFN-like molecule, limitin, was recently identified and revealed to suppress B lymphopoiesis through the IFN-alphabeta receptor, although it lacked growth suppression on myeloid and erythroid progenitors. Here we have studied diverse effects of limitin on T lymphocytes and compared limitin with previously known IFNs. Like IFN-alpha and -beta, limitin modified immunity in the following responses. It suppressed mitogen- and Ag-induced T cell proliferation through inhibiting the responsiveness to exogenous IL-2 rather than suppressing the production of IL-2. In contrast, limitin enhanced cytotoxic T lymphocyte activity associated with the perforin-granzyme pathway. To evaluate the effect of limitin in vivo, a lethal graft-versus-host disease assay was established. Limitin-treatment of host mice resulted in the enhancement of graft-versus-host disease. Limitin did not influence thymocyte development either in fetal thymus organ cultures or in newborn mice injected with limitin-Ig, suggesting that limitin is distinguishable from IFN-alpha and -beta. From these findings, it can be speculated that the human homolog of limitin may be applicable for clinical usage because of its IFN-like activities with low adverse effects on, for example, T lymphopoiesis, erythropoiesis, and myelopoiesis.
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PMID:A new IFN-like cytokine, limitin, modulates the immune response without influencing thymocyte development. 1154 1


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