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PubMed1992

Heart allografts in murine systems. The differential activation of Th2-like effector cells in peripheral tolerance.

Activated CD4+ Th2 cells release cytokines (IL-4,-10) that block activation & cytokine (IL-2/IFN-gamma) release by proinflammatory T (CD4+,CD8+) effector cells. To test the hypothesis that peripheral tolerance to alloantigen is linked to differential activation of CD4+ Th2 cells we measured cytokine transcripts in heart grafts (C57BL/10----C3H/HeJ) and spleens of mice rendered "tolerant" by donor-specific blood transfusion, anti-CD4 mAb pretreatment, and cyclosporine administration. The expression of IL-2/IFN-gamma transcripts was reduced greater than 90% in grafts from tolerant recipients. IL-4/IL-10 transcripts were generally enhanced and persisted in graft and recipient spleen. Accordingly adoptive transfer studies were performed to determine whether Th2-like effectors, which express Fc receptors (FcR), mediate suppression in this model. Unfractionated mononuclear cells (MC) (5 x 10(6), isolated from spleens of heart graft recipients made tolerant by DST, prolonged the survival of test grafts greater than 90 days in irradiated (680 rads) recipients reconstituted with a sufficient number of MC from spleens of naive C3H to precipitate rejection of the test graft in 18.2 days (MST, n = 5). Conversely adoptive transfer of inocula depleted of FcR+ cells on immune complex columns or with anti-FcR mAb 24G2 caused test grafts to be rejected in 8-11 days. These results suggest that peripheral tolerance to alloantigen may be linked to differential activation of Th2 cells that induce anergy by suppression. The possibility that Th2-like effectors mediate peripheral tolerance to self is discussed.

Animals↗
PubMed1992

Herpetic stromal keratitis: an immunopathologic disease mediated by CD4+ T lymphocytes.

To investigate the role of T cell subsets in the development of herpetic stromal keratitis (HSK) in a well defined model, we used an adoptive transfer approach in which thymectomized and T cell-depleted mice [T(-)] were reconstituted with different numbers of syngeneic immune T lymphocytes after topical corneal challenge with RE strain of herpes simplex virus-1. In vitro stimulated or unstimulated immune T cells obtained from cervical and retropharyngeal lymph nodes of mice with HSK were used in adoptive transfer experiments. Although T(-) mice developed an initial epithelial inflammation, stromal keratitis did not occur. Reconstitution experiments revealed that mice that received 2 x 10(7) or more unfractionated immune T cells could develop HSK lesions with severity comparable to immuno-competent control mice. In mice receiving CD8(+)-depleted populations, even fewer cells (5 x 10(6)/mouse) were able to induce significant HSK. In contrast, mice that received similar or increased numbers of cells depleted of CD4+ T lymphocytes did not develop HSK. Immune T lymphocytes transferred to mice that were mock infected on the cornea did not develop HSK, indicating that the immunopathogenic cells were virus specific and not merely reacting to autoantigens. Histopathologic examination of the diseased corneas demonstrated that the stromal inflammation in euthymic normal and T(-)-reconstituted mice was characterized by extensive polymorphonuclear leukocyte infiltration. Scattered lymphocytes, and occasional macrophages also were observed. These results provide further evidence that HSK represents an immunopathologic process mediated mainly by CD4+ T cells.

Animals↗
PubMed1992

Re-examination of peripheral blood T cell subsets in dysthyroid orbitopathy.

Patients with dysthyroid orbitopathy (DO) were grouped according to a multifactorial assessment of disease severity and the rate of disease progression. Using this system and flow cytometric measurements of T cell subsets in the peripheral blood, a significant increase in the percentage of CD4+ lymphocytes correlated with disease severity in DO patients with progressive disease. These observations are consistent with the hypothesis that the CD4+ peripheral blood T helper cells play a significant role in the progression of DO.

Adult↗
PubMed1992

Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii.

C57BL/6 mice chronically infected with an avirulent strain (ME-49) of Toxoplasma gondii were used to study the mechanisms by which T lymphocytes and IFN-gamma prevent reactivation of latent infection. Infected animals were treated with mAb, either anti-CD8, anti-CD4, anti-CD4 plus anti-CD8, anti-IFN-gamma, or anti-CD4 plus anti-IFN-gamma and the mice followed for survival, histopathology, cyst numbers, and spleen cell cytokine responses. In agreement with previously published findings, treatment with anti-IFN-gamma antibodies fully reactivated the asymptomatic infection, inducing massive necrotic areas in the brain with the appearance of free tachyzoites and death of all animals within 2 wk. Mice treated with the combination of anti-CD4 plus anti-CD8 antibodies showed augmented pathology and mortality nearly identical to the anti-IFN-gamma- treated animals. In contrast, treatment with anti-CD4 or anti-CD8 mAb alone failed to result in significantly enhanced brain pathology or mortality. In additional experiments, full reactivation of infection was observed in mice treated with anti-CD4 plus anti-IFN-gamma indicating that CD4+ lymphocytes are not required for the pathology resulting from IFN-gamma neutralization. Cytokine measurements on parasite Ag-stimulated spleen cells from mAb-treated mice indicated that both CD4+ and CD8+ cells produce IFN-gamma whereas only CD4+ cells contribute to parasite Ag-induced IL-2 synthesis. Together, these results suggest that CD4+ and CD8+ lymphocytes act additively or synergistically to prevent reactivation of chronic T. gondii infection probably through the production of IFN-gamma.

Animals↗
PubMed1992

Induction and suppression of delayed-type hypersensitivity to non-MHC antigens during lethal graft-versus-host reaction.

A delayed-type hypersensitivity reaction (DTH) to non-MHC Ag was detected during a lethal graft-vs-host reaction (GVH) induced by incompatibility for non-MHC Ag alone. In this model, when appropriate doses of B10.D2 bone marrow and lymphoid cells are grafted to irradiated (DBA/2 x B10.D2)F1 recipients, the ensuing GVH, directed against those DBA/2 non-MHC Ag absent from the B10.D2 background, results in virtually 100% mortality in less than 3 mo; donor alloimmunization against the host histocompatibility Ag considerably reduces mortality, and survival rates of 80 to 100% are common. The experiments reported here show that: 1) the cell responsible for DTH induction expresses the CD4+ CD8- phenotype; 2) CD4+ cells likewise seem to play a predominant role in the pathology of lethal GVH in this genetic combination; 3) the alloimmunization protocol that abrogates mortality also abolishes GVH-associated DTH; and 4) this suppressive effect, as shown elsewhere for the protection against mortality, is mediated by CD4- CD8- "double negative" Thy-1+ CD3+ T suppressor cells. Thus, there is a good parallel between lethal GVH and its associated DTH as concerns both induction and suppression of the two phenomena, suggesting that mortality and DTH may represent different manifestations of a common underlying mechanism. Initiation of the effector phase of DTH in the adoptive transfer model seems to be dependent on the presence of a Thy-1+ double-negative cell in the transfer inoculum; the possible relationship of this double-negative cell to the Th-1-type CD4+ DTH-mediating cell recently shown to induce lethal GVH is discussed.

Animals↗
PubMed1992

Murine AIDS superantigen reactivity of the T cells bearing V beta 5 T cell antigen receptor.

A B cell line, B6-1710, that expresses the defective virus known to induce murine AIDS stimulates a large fraction of nonprimed splenic T cells. Analysis of the T cell population responding to the B6-1710 for TCR V beta-chain usage revealed that, in addition to the previously reported V beta 5-chain-positive T cells, T cells bearing V beta 11 and V beta 12 are also specifically enriched. We have established V beta 5+ T cell lines, clones, and hybridomas expressing identical TCR with different CD4/CD8 phenotypes and demonstrated that T cell reactivity to B6-1710 is, although not absolute, dependent on the presence of CD4 molecules. Further analysis of T cell hybridomas with known J beta-chain usage revealed that D beta- and J beta-chain usage do not play crucial roles in T cell reactivity to B6-1710 B cells. However, T cell hybridomas derived from TCR-V beta gene transgenic mice were found to be heterogeneous for their reactivity to B6-1710, suggesting that the V alpha-chains associating with the transgenic V beta-chain determine T cell responsiveness to B6-1710. These data clearly demonstrate that T cell reactivity to a murine AIDS virus expressing B cell line resembles that previously reported for Mls-like superantigens.

Animals↗
PubMedDate not supplied

Characterization of human heart-infiltrating cells after transplantation. VI. Differences in the cytokines produced by individual CD4+ cloned T-cell lines with apparently identical antiidiotype-like reactivity.

Studies of cultures and cloned T-cell lines from mononuclear cell infiltrates in cardiac biopsy specimens have provided a unique resource to study the cellular basis of human organ allograft rejection. Our laboratory has previously shown that biopsy specimens placed on autologous donor MHC-class-II-specific cloned T-cell lines from previous cardiac biopsies led to the isolation of cloned T-cell lines, which appeared to be functionally "antiidiotypic" in nature. Detailed functional analysis of such CD4+ individual antiidiotype-reactive cloned T-cell lines revealed that although some augmented the proliferative response of autologous idiotype-bearing cloned T-cell lines against donor stimulator cells, others markedly suppressed the proliferative response; thus, although each of these antiidiotype-like reactive cloned T-cell lines appears to specifically react with the same idiotype-bearing donor MHC-class-II-specific cloned T-cell line, they were functionally heterogeneous. Analysis of cytokines secreted by these individual clones showed that the antiidiotype-reactive cloned T-cell lines that suppressed the response of idiotype-bearing cells appear to secrete predominantly interferon gamma, whereas those antiidiotype-reactive cloned T-cell lines that augmented the response do not secrete interferon gamma but secrete interleukin-2, -4, and -6. These preliminary data suggest that differences in the predominant cytokines secreted by these individual antiidiotype-reactive cloned T-cell lines may account for their functional differences.

Antibodies, Anti-Idiotypic↗
PubMed1992

Alveolar macrophage populations are distorted in immunocompromised patients with pneumonitis.

Alveolar macrophages (AM) were obtained by bronchoalveolar lavage (BAL) from patients presenting with pneumonitis: 30 human immunodeficiency virus (HIV)-infected individuals and 12 transplant recipients. Nine normal volunteers acted as controls. The cells were washed and cytospins prepared. Monoclonal antibodies (MoAbs) and immunoperoxidase methods were used to analyse the expression of HLA-DR molecules as well as phenotypic macrophage markers. P values apply to the differences between medians using the Mann-Whitney test. Median percentages of macrophages, lymphocytes and neutrophils were similar in all three groups. No differences were found in the median percentages of macrophages expressing the monocyte phenotype (MoAb UCHM1, CD14). However, in HIV-infected patients and transplant recipients a median of only 45% of macrophages expressed the pan-macrophage phenotype identified by MoAb EBM11 (CD68) in contrast with 98% in the normal volunteers. The AM population expressing the dendritic cell marker (MoAb RFD1) was also markedly reduced in both groups of immunocompromised patients (2 vs 28% in normal volunteers). Transplant recipients had significantly more phagocytic cells identified by MoAb RFD7 than the HIV-infected patients (25 vs 2%), but the numbers were still low when compared with the volunteers (48%). HLA-DR expression on BAL cells was reduced by 90% in both immunocompromised groups. For the transplant recipients, severity of pneumonitis was correlated with expression of dendritic cell marker RFD1, (Spearman's rank correlation r = 0.538, p less than 0.05) and pan-macrophage marker EBM11 (r = 0.581, p less than 0.05), while no such correlation was found in HIV-infected patients. These results suggest that a defective macrophage population is probably a serious factor contributing to immunosuppression.

Adult↗
PubMed1992

The diversity of the CD4+ T cell response in influenza.

We have analyzed the specificity and structural basis of the CD4+ helper T cell (Th) response of BALB/c mice to influenza virus. We find that many of the viral proteins are recognized by Th, and for one of these proteins we have defined eight distinct Th determinants. Moreover, Th that recognize a single determinant use structurally diverse T cell receptors, and display many unique specificities for the same determinant. These findings demonstrated extensive diversity at several levels of the Th response to influenza virus.

Amino Acid Sequence↗
PubMed1992

Lethal graft-versus-host disease in mice directed to multiple minor histocompatibility antigens: features of CD8+ and CD4+ T cell responses.

Lethal graft-versus-host disease (GVHD) can be induced in MHC-matched strain combinations which differ in their expression of multiple minor histocompatibility (H) antigens. It has been shown that CD8+ T cells play an important role in the development of disease directed to the minor H antigens, and that initial indications were that highly purified preparations of these cells were capable of mediating GVHD, without apparent 'help' from mature donor-derived CD4+ T cells. To further strengthen this hypothesis, the current study was undertaken with the B10.BR----CBA strain combination in which irradiated recipient mice were additionally treated with an anti-CD4 monoclonal antibody, as a single or repeated injection, to minimize the presence of either residual host CD4+ cells or recently generated donor-derived CD4+ cells at later stages of disease development. The results indicate that these treatments do not affect the GVHD outcome and that the CD8+ cells are indeed capable of inducing disease independent of CD4+ 'help'. The addition of donor CD4+ T cells in the inoculum, however, does enhance the potential of these CD8+ cells, and is observed with both low and high dosages of CD4+ cells. CD4+ T cells, on their own, have also been observed to cause GVHD directed to minor H antigens in certain strain combinations, and their response has been further characterized in this study. Results indicate that CD4+ cells capable of mediating GVHD in the B10.D2----DBA/2 strain combination can do so over a wide range of recipient irradiation exposures. The transfer of high dosages of CD4+ cells only shortens survival times of the recipients and does not afford any apparent protection phenomenon as previously observed in CD4+ cell mediated anti-class II MHC GVHD. The study also indicates that neither CD4+ nor CD8+ cells responsible for GVHD directed to minor H antigens seem capable of targeting host stem cell elements.

Animals↗
PubMed1992

[Differentiation of fetal lymphocytes with the DP-(dipeptidylpeptidase-) IV technique].

The knowledge about the ontogenicity of the human immune system based on animal experiments. In this study expulsed fetus of women with sponeous and arteficial abortions were analysed because of the content of T4(+)-lymphocytes in the lymphatic tissues. The thymus, spleen, and a piece of the bone marrow were dissected, homogenised and the lymphocytes were separated. The identification of the T4+ cells was performed by the cytochemical staining of dideptidyl peptidase IV (DP IV). It could established that from the 15th to the 26th week of gestation the number of T4+ cells increased in the thymus and spleen but not in the bone marrow. In cases with rubella infection was the number of T4+ cells in the spleen increased if the fetus have had no signs of embryopathy.

Adolescent↗
PubMed1992

Human myoblasts as antigen-presenting cells.

Human myoblasts, cultured from muscle and purified to greater than 95%, were investigated for their capacity to act as facultative APC. The myoblasts reacted with antidesmin mAb and had the capacity to fuse into multinucleated myotubes in appropriate medium. The expression of HLA class I, HLA-DR, HLA-DP, HLA-DQ, intercellular adhesion molecule-1 (ICAM-1/CD54), lymphocyte function-associated (LFA) molecules LFA-1 (CD11a/CD18), LFA-2 (CD2), and LFA-3 (CD58) was investigated by FACS analysis before and after induction for various times with human rIFN-gamma, TNF-alpha, or both. Without cytokine induction, myoblasts expressed only HLA-class I and LFA-3. IFN-gamma alone or in combination with TNF-alpha induced the expression of HLA-DR and ICAM-1 reaching a plateau after 48 h, followed by HLA-DP and even later HLA-DQ. TNF-alpha alone induced only ICAM-1. The functional capacity of myoblasts to present Ag to CD4+ T cells was investigated using autologous T cell lines specific for tuberculin, tetanus toxoid, and human myelin basic protein. Noninduced myoblasts or myoblasts treated with TNF-alpha alone could not present any of these Ag to the T cells. However, myoblasts treated with IFN-gamma induced Ag-specific proliferation. In the presence of relevant Ag, myoblasts were killed by the T cells as observed by microscopy and measured by 51Cr release. Ag-specific T cell proliferation and myoblast killing was inhibited in the presence of anti-DR mAb. These results suggest that human myoblasts may act as facultative APC during local immune reactions in muscle.

Antigen-Presenting Cells↗
PubMed1992

CD4 lymphocyte count as an indicator of delay in seeking human immunodeficiency virus-related treatment.

BACKGROUND: As many as half of patients infected with the human immunodeficiency virus who are medically eligible for Pneumocystis prophylaxis and zidovudine treatment have not received these treatments. We used the CD4 lymphocyte count as an indicator of delay in seeking treatment among patients infected with human immunodeficiency virus and assessed whether insurance status was associated with the stage of illness when care is initiated. METHODS: Data from 96 patients who initiated medical care at a university acquired immunodeficiency syndrome clinic from August 1989 to January 1991 were retrospectively reviewed. RESULTS: Patients initiated care at a relatively late stage of illness (mean CD4 lymphocyte count, 0.37 x 10(9)/L [369/mm3]), and 29% were below the threshold for Pneumocystis prophylaxis. Patients with private insurance had significantly lower CD4 counts (mean, 0.27 x 10(9)/L) than did individuals with public insurance (mean, 0.46 x 10(9)/L). CD4 counts did not increase during the 18-month study period. CONCLUSIONS: The majority of patients infected with human immunodeficiency virus are eligible for medical therapy and could benefit by initiating care sooner. Private insurance was not associated with initiating early care, supporting anecdotal reports that some privately insured individuals may be reluctant to seek care for a human immunodeficiency virus-related condition.

Adult↗
PubMed1992

Human CD4+ T cells expressing CD45RA acquire the lymphokine gene expression of CD45RO+ T-helper cells after activation in vitro.

CD4+ T cells were separated into subpopulations according to their expression of different isoforms of the CD45R molecule, i.e. CD45RA and CD45RO. The separated cells were activated with staphylococcal enterotoxin A (SEA) in the presence of formalin fixed Raji cells. Each set of cells was activated twice with a 6-day interval, and the lymphokine gene expression during the first 3 days after initiation of each stimulation was followed by use of polymerase chain reaction (PCR) technology. The lymphokine messenger RNA (mRNA) profiles were found to differ between the subsets, since after the first stimulation the CD45RA+ cells produced mRNA encoding interleukin-2 (IL-2) and IL-1 alpha, whereas the CD45RO+ cells transcribed genes for IL-1 alpha, IL-2, IL-4, IL-5 and interferon-gamma (IFN-gamma). After 6 days of SEA stimulation both populations were mainly CD45RO reactive, and when restimulated displayed the lymphokine mRNA profile restricted to this subset. These results indicate that the CD45RA subset is a precursor of the CD45RO and further strengthen the hypothesis that the former cell population represents naive whereas the latter subset represents memory T cells within the CD4 subset.

Antigens, CD↗
PubMed1992

HIV and AIDS.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Analysis of the basis of resistance and susceptibility of CD4+ T cells to human immunodeficiency virus (HIV)-gp120 induced anergy.

The resistance and susceptibility of T cells to human immunodeficiency virus (HIV)-gp120 induced anergy was examined. Antigen-dependent proliferation of polyclonal T cells was markedly inhibited by gp120, whereas from the analysis of monoclonal populations, T cells resistant to the effects of gp120 could be identified. Similarly, exposure of monoclonal T cells to gp120 in the absence of accessory cells, also demonstrated that some T cells could resist the induction of anergy. Loss of antigen recognition was associated with phenotypic modulation of CD3 and CD28, which was not observed in T cells resistant to functional inactivation by gp120. Modulation of CD4 was not related to induction of anergy in the monoclonal T cells examined in this study. Inhibition of T-cell responses by anti-CD4 antibodies was compared to that by gp120. Anti-CD4 antibodies, which cross-compete with gp120 for binding to CD4, inhibited the response to antigen of monoclonal T cells. In contrast, no tolerogenic signals were delivered by pretreating T cells with the anti-CD4 antibodies in the absence of accessory cells, indicating that inhibition was due to abrogation of the interaction of CD4 with major histocompatibility complex (MHC) class II molecules expressed on accessory cells. Although the free CD4-binding region peptide of gp120 could inhibit polyclonal T-cell responses, only the carrier-bound peptide was able to modulate cloned T cells, suggesting a conformational requirement for functional inactivation through engagement of CD4. The results reported here using clonal CD4+ T-cell populations demonstrate that effects of gp120 on antigen-dependent proliferation are not uniform, and that therapeutic intervention might be directed at T-cell populations identified as susceptible to HIV-gp120 induced anergy.

Antigens, CD↗