Biomedical subjects

F T Hakim

Publications and source records attributed to F T Hakim.

9 recordsLinked to original sources

PubMed1992

Regulation of graft-versus-host-reaction by Mlsa-reactive donor T cells.

Injection of A/J splenocytes (H-2Dd, Mlsc) into unirradiated (A/J x CBA)F1 (BAF1) host mice (H-2Dd/k, Mlsd) results in an acute suppressive graft-vs.-host reaction (GVHR), characterized by immune dysfunction and appreciable donor cell engraftment; injection of the CBA/J parent (H-2Dk, Mlsd), which recognizes no Mls disparity in the host, results in little or no GVHR. Furthermore, the Mlsa-reactive V beta 6 and V beta 8.1 T cell subsets in A/J T cells expand significantly in the GVHR host. Finally, depletion of V beta 6+ and V beta 8.1+ from the A/J population abrogates the proliferative response to BAF1 in vitro and the development of GVHR in vivo. Thus, the response to Mls determinants can contribute to the generation of a GVHR.

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PubMed1991

CD8+ T cells from mice vaccinated against Toxoplasma gondii are cytotoxic for parasite-infected or antigen-pulsed host cells.

Mice vaccinated with a live temperature sensitive mutant (TS-4) of Toxoplasma gondii develop complete resistance to subsequent challenge with a highly virulent Toxoplasma strain (RH). Because CD8+ T cells have been demonstrated to be critical to this protective immunity in vivo, the involvement of cytotoxic T lymphocytes in the killing of infected cells in vaccinated mice was investigated. After restimulation in vitro, splenic T cells from vaccinated mice of either the BALB/c or C57BL/6 strains were found to kill syngeneic bone marrow-derived macrophages infected with TS-4 tachyzoites or preincubated with soluble T. gondii Ag. Unimmunized control mice or mice vaccinated with heat-killed TS-4 tachyzoites failed to generate significant CTL activity in vitro. Moreover, the observed lytic reaction was found to be target specific, not killing uninfected or unpulsed macrophages even when included as bystanders in the assay. Target lysis did not depend on the production by the effector cells of either a cytotoxic supernatant factor or IFN-gamma. Depletion of CD8+ cells from the splenic effector cell population, however, abrogated the cytotoxic activity, whereas depletion of CD4+ cells had little effect. The MHC restriction of the Toxoplasma-specific cytolytic reaction was confirmed in studies using effector cells from BALB/c mice and targets from congenic or mutant haplotype strains. These experiments indicated that target killing is primarily restricted by genes mapping within the H-2D/Ld loci. Together, these results establish MHC-restricted cytolysis as a major parameter of CD8+ effector function against T. gondii and indicate that, in the case of this protozoan, Ag presentation to CD8+ lymphocytes can occur as a result of either processing within infected cells or exogenous uptake of parasite Ag.

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PubMed1991

Repopulation of host lymphohematopoietic systems by donor cells during graft-versus-host reaction in unirradiated adult F1 mice injected with parental lymphocytes.

The graft-vs-host reaction (GVHR) generated by the injection of parental lymphocytes into unirradiated immune-competent F1 hosts is characterized by an acute loss of immune functions, an attack on host tissues, and a gradual recovery of function. Flow cytometric analysis of the donor- and host-derived splenic populations during the course of acute dysfunction and gradual recovery revealed a complex pattern of changes in lymphoid and myeloid populations that resulted in the repopulation of the host with donor-derived cells. Initially, donor-derived T cell populations expanded, particularly CD8+ T cells. Next, host T cell and B cell populations disappeared. Finally, donor-derived cells repopulated the lymphohematopoietic system in the sequence myeloid populations, B cells, and, after a protracted period, T cells. The recovery of immune functions following GVHR-induced immune deficiency was associated with this repopulation of the spleen by donor-derived cells. Donor repopulation of the host lymphohematopoietic system required the presence of both CD4 and CD8 cells in the original donor inoculum. Depletion of donor CD4 populations precluded development of GVHR or any donor engraftment; depletion of CD8 cells resulted in engraftment solely of donor CD4 populations.

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PubMed1991

Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine.

BALB/c mice vaccinated with a temperature-sensitive mutant (TS-4) of Toxoplasma gondii develop complete resistance to lethal challenge with a highly virulent toxoplasma strain (RH). This immunity is known to be dependent on IFN-gamma synthesis. In vitro and in vivo T cell depletions were performed in order to identify the subsets responsible for both protective immunity and IFN-gamma production. When stimulated with crude tachyzoite Ag in vitro, CD4+ cells from vaccinated mice produced high levels of TH1 cytokines (IL-2 and IFN-gamma) but not TH2 cytokines (IL-4 and IL-5). CD8+ cells, in contrast, produced less IFN-gamma and no detectable IL-2. Nevertheless, they could be induced to synthesize IFN-gamma when exposed in culture to exogenous IL-2. In vivo treatment with anti-CD4 plus anti-CD8 or anti-IFN-gamma antibodies during challenge infection completely abrogated resistance to T. gondii. In contrast, treatment with anti-CD4 alone failed to reduce immunity, whereas anti-CD8 treatment partially decreased vaccine-induced resistance. These results suggest that although IFN-gamma and IL-2-producing CD4+ lymphocytes are induced by vaccination, IFN-gamma-producing CD8+ T cells are the major effectors of immunity in vivo. Nevertheless, CD4+ lymphocytes appear to play a synergistic role in vaccine-induced immunity, probably through the augmentation of IFN-gamma synthesis by the CD8+ effector cells. This hypothesis is supported by the observation that when giving during vaccination, as opposed to after challenge, anti-CD4 antibodies are capable of blocking protective immunity.

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PubMed1990

Murine cytomegalovirus infection can enhance hybrid resistance through modulation of host natural killer activity.

Studies were undertaken to assess the effect of murine cytomegalovirus (MCMV) in two different models involving injection of parental cells into F1 hosts. In both of these systems, MCMV-induced enhancement of hybrid resistance was found. In the first model, parent-into-F1 graft-vs-host reaction, MCMV infection of (C57BL/6 x C3H)F1 (B6C3F1) hosts was found to prevent the GVHR normally induced by injection of B6 parental splenocytes into the F1 hosts. The second model involved injection of parental bone marrow into lethally irradiated B6C3F1 and (C57BL/6 x DBA/2)F1 (B6D2F1) hosts. These irradiated hosts are known to exhibit resistance to engraftment by parental C57BL/6 (B6) bone marrow. This resistance was found to be markedly enhanced by injection of the hosts with MCMV 3 days before irradiation and bone marrow injection. In contrast, engraftment into B6C3F1 hosts of syngeneic marrow, or bone marrow from the C3H parent, was not affected by MCMV infection. Engraftment of DBA/2 marrow into B6D2F1 hosts was reduced at lower doses of injected marrow, suggesting enhanced resistance against the minor Hh Ag Hh-DBA. To test whether the MCMV-induced enhancement of resistance was mediated by NK cells, splenic NK activity (YAC-1 killing) and frequency (NK1.1 staining) were assessed. Both parameters were found to be elevated at 3 days after MCMV infection but to return to normal levels by 9 days. B6 bone marrow engraftment was in fact found to be normal when the marrow was administered to F1 mice 9 days after MCMV infection. Furthermore, anti-asialoGM1 administration prevented MCMV-induced enhancement of resistance to marrow engraftment. Thus, the NK enhancement resulting from MCMV infection appears to play a major role in the enhanced HR observed in the marrow engraftment model. This effect may be of importance in clinical bone marrow transplantation, a situation in which patients are susceptible to viral infection.

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PubMed1990

Alterations in T cell-derived colony-stimulating factors associated with GVH-induced immune deficiency.

Injection of parental C57BL/10 spleen cells into unirradiated immune-competent (B10 x B10.BR)F1 hosts has been demonstrated to produce a graft-vs.-host-induced immune deficiency in T cell-mediated functions, including mitogen or alloantigen stimulated proliferation or cytotoxic T cell generation. The production of T cell-derived lymphokines affecting hematopoiesis was also altered during GVH. During the first two weeks of GVH, IL-3 and particularly GM-CSF were produced spontaneously; in subsequent weeks, the spontaneous production dropped to normal or subnormal levels. CSF content in concanavalin A-stimulated splenic supernatants was reduced at weeks 1-2, and declined to less than 5% of normal levels by 3-4 weeks of GVH. This decline in CSF content was correlated with a decrease in immune function as assessed by concanavalin A-stimulated IL-2 production and by generation of cytotoxic T lymphocytes. Concurrent with the recovery of immune function during GVH weeks 8-15, mitogen-stimulated production of CSF returned to normal levels. In addition to the decrease in CSF production identified in acute suppressive GVH, CSF content in concanavalin A-stimulated splenic supernatants was also decreased in chronic stimulatory GVH, generated in the strain combination (B6 x B6bm1)F1----(B6bm1 x B6bm12)F1. This decrease in CSF production correlated with a decrease in self-restricted T helper cell function. Finally, a decrease in both immune function and CSF production capacity was observed in the acute GVH following allogeneic (minor histocompatibility loci) bone marrow transplantation into irradiated hosts.

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PubMed1990

Factors contributing to the decrease in concanavalin A-induced colony-stimulating factors in acute suppressive graft-versus-host disorder.

We have recently demonstrated that IL-3 and GM-CSF content in concanavalin A--stimulated splenic cultures was severely depressed for several weeks in mice undergoing an acute graft-vs.-host reaction (GVHR). Several factors contributed to this decrease in CSF levels at different points in the first 10 weeks of GVH. Myeloid lineage cells, both GM-CFU and Mac-1+ cells, increased in the spleen during GVH weeks 3-6, and (125I)-GM-CSF binding by spleen cells increased 10 fold--hence CSF content in supernatants was probably reduced by local consumption during these weeks. During GVH weeks 3-12, levels of all T cells--and of L3T4+ T cells, in particular--were reduced, limiting production of T cell derived lymphokines. Finally, during the first six weeks of GVH, immune suppression was found in cocultures of normal F1 and GVH spleens. Furthermore, during weeks 3-5, nonspecific suppression was found, affecting CSF production not only by normal host spleens but also by parental donor or unrelated spleen cells as well.

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PubMed1986

Abrogation of hybrid resistance to bone marrow engraftment by graft-vs-host-induced immune deficiency.

Lethally irradiated F1 mice, heterozygous at the hematopoietic histocompatibility locus Hh-1, which is linked with H-2Db, reject bone marrow grafts from H-2b parents. This hybrid resistance (HR) is reduced by prior injection of H-2b parental spleen cells. Because injection of parental spleen cells produces a profound suppression of F1 immune functions, we investigated whether parental-induced abrogation of HR was due to graft-vs-host-induced immune deficiency (GVHID). HR was assessed by quantifying engraftment of H-2b bone marrow in F1 mice with the use of splenic [125I]IUdR uptake; GVHID, by the ability of F1 spleen cells to generate cytotoxic T lymphocytes (CTL) in vitro. We observed a correlation in the time course and spleen cell dose dependence between loss of HR and GVHID. Both GVHID and loss of HR were dependent on injection of parental T cells; nude or T-depleted spleen cells were ineffective. The injection of B10 recombinant congenic spleens into (B10 X B10.A)F1 mice, before grafting with B10 marrow, demonstrated that only those disparities in major histocompatibility antigens that generated GVH would result in loss of HR. Thus, spleens from (B10 X B10.A(2R]F1 mice (Class I disparity only) did not induce GVHID or affect HR, whereas (B10 X B10.A(5R))F1 spleens (Class I and II disparity) abrogated CTL generation and HR completely. GVHID produced by a class II only disparity, as in (B10 X B10.A(5R))F1 spleens injected into (B6bm12 X B10.A(5R))F1 mice, was also sufficient to markedly reduce HR to B10 bone marrow. This evidence that GVHID can modulate hematopoietic graft rejection may be relevant to the mechanisms of natural resistance to marrow grafts in man.

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PubMed1986

Hereditary joint disorder in progressive ankylosis (ank/ank) mice. II. Effect of high-dose hydrocortisone treatment on inflammation and intraarticular calcium hydroxyapatite deposits.

Mice homozygous for the progressive ankylosis trait develop an inflammatory joint disorder associated with the intraarticular deposition of calcium hydroxyapatite. When affected (ank/ank) mice were treated with high doses of hydrocortisone, synovitis receded, development of cartilaginous and bony osteophytes halted, and calcium hydroxyapatite accumulated in and distended the synovial spaces. No changes, however, occurred in the joint morphology of hydrocortisone-treated normal (ank/+) mice. Since inhibition of inflammation by hydrocortisone treatment did not block apatite accumulation, intraarticular deposition of hydroxyapatite occurs independent of inflammation in progressive ankylosis.

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