Prevention of collagen-induced arthritis by gene delivery of soluble p75 tumour necrosis factor receptor.
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Collagen type II-induced arthritis (CIA) in DBA/1 mice can be passively transferred to SCID mice with spleen B- and T-lymphocytes. In the present study, we show that infection ex vivo of splenocytes from arthritic DBA/1 mice with a retroviral vector, containing cDNA for the soluble form of human p75 receptor of tumour necrosis factor (TNF-R) before transfer, prevents the development of arthritis, bone erosion and joint inflammation in the SCID recipients. Assessment of IgG subclass levels and studies of synovial histology suggest that down-regulating the effector functions of T helper-type 1 (Th1) cells may, at least in part, explain the inhibition of arthritis in the SCID recipients. In contrast, the transfer of splenocytes infected with mouse TNF-alpha gene construct resulted in exacerbated arthritis and enhancement of IgG2a antibody levels. Intriguingly, infection of splenocytes from arthritic DBA/1 mice with a construct for mouse IL-10 had no modulating effect on the transfer of arthritis. The data suggest that manipulation of the immune system with cytokines, or cytokine inhibitors using gene transfer protocols can be an effective approach to ameliorate arthritis. (+info)
Thymic selection by a single MHC/peptide ligand: autoreactive T cells are low-affinity cells.
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In H2-M- mice, the presence of a single peptide, CLIP, bound to MHC class II molecules generates a diverse repertoire of CD4+ cells. In these mice, typical self-peptides are not bound to class II molecules, with the result that a very high proportion of H2-M- CD4+ cells are responsive to the various peptides displayed on normal MHC-compatible APC. We show here, however, that such "self" reactivity is controlled by low-affinity CD4+ cells. These cells give spectacularly high proliferative responses but are virtually unreactive in certain other assays, e.g., skin graft rejection; responses to MHC alloantigens, by contrast, are intense in all assays. Possible explanations for why thymic selection directed to a single peptide curtails self specificity without affecting alloreactivity are discussed. (+info)
Rapid death of adoptively transferred T cells in acquired immunodeficiency syndrome.
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Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) probably play the major role in controlling HIV replication. However, the value of adoptive transfer of HIV-specific CTL expanded in vitro to HIV+ patients has been limited: this contrasts with the success of CTL therapy in treating or preventing Epstein-Barr virus and cytomegalovirus disease after bone marrow transplantation (BMT). We investigated the fate of expanded HIV-specific CTL clones in vivo following adoptive transfer to a patient with acquired immunodeficiency syndrome (AIDS). Two autologous CTL clones specific for HIV Gag and Pol were expanded to large numbers (>10(9)) in vitro and infused into an HIV-infected patient whose viral load was rising despite antiretroviral therapy. The fate of one clone was monitored by staining peripheral blood mononuclear cells (PBMCs) with T-cell receptor-specific tetrameric major histocompatibility complex (MHC)-peptide complexes. Although the CTL transfer was well tolerated, there were no significant changes in CD4 and CD8 lymphocyte counts and virus load. By tracking an infused clone using soluble MHC-peptide complexes, we show that cells bearing the Gag-specific T-cell receptors were rapidly eliminated within hours of infusion through apoptosis. Thus, the failure of adoptively transferred HIV-specific CTL to reduce virus load in AIDS may be due to rapid apoptosis of the infused cells, triggered by a number of potential mechanisms. Further trials of adoptive transfer of CTL should take into account the susceptibility of infused cells to in vivo apoptosis. (+info)
Chlamydia infections and heart disease linked through antigenic mimicry.
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Chlamydia infections are epidemiologically linked to human heart disease. A peptide from the murine heart muscle-specific alpha myosin heavy chain that has sequence homology to the 60-kilodalton cysteine-rich outer membrane proteins of Chlamydia pneumoniae, C. psittaci, and C. trachomatis was shown to induce autoimmune inflammatory heart disease in mice. Injection of the homologous Chlamydia peptides into mice also induced perivascular inflammation, fibrotic changes, and blood vessel occlusion in the heart, as well as triggering T and B cell reactivity to the homologous endogenous heart muscle-specific peptide. Chlamydia DNA functioned as an adjuvant in the triggering of peptide-induced inflammatory heart disease. Infection with C. trachomatis led to the production of autoantibodies to heart muscle-specific epitopes. Thus, Chlamydia-mediated heart disease is induced by antigenic mimicry of a heart muscle-specific protein. (+info)
Adoptive transfer of genetically modified macrophages elucidated TGF-beta-mediated 'self-defence' of the glomerulus against local action of macrophages.
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TGF-beta has several anti-inflammatory properties which may be relevant to prevention of or recovery from acute glomerular inflammation. Using genetically modified mesangial cells and a technique for in vivo macrophage transfer, this article provides evidence for TGF-beta-mediated 'self-defence' of the glomerulus against macrophages. Rat mesangial cells stably transfected with TGF-beta1 showed a blunted response to the macrophage-derived, proinflammatory cytokine IL-1beta. In contrast, mesangial cells expressing the dominant-interfering TGF-beta receptor showed an enhanced response to IL-1. Similarly, externally added TGF-beta1 inhibited the cytokine response of normal glomeruli, and isolated nephritic glomeruli producing active TGF-beta1 showed a depressed response to IL-1beta, compared to normal glomeruli. Consistent with these in vitro results, in vivo transfer of activated macrophages revealed that the TGF-beta-producing glomeruli are insensitive to the effector action of macrophages. These results indicate that TGF-beta1 functions as an endogenous 'defender' that counteracts local action of activated macrophages in the glomerulus. (+info)
Efficient IgG-mediated suppression of primary antibody responses in Fcgamma receptor-deficient mice.
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IgG antibodies can suppress more than 99% of the antibody response against the antigen to which they bind. This is used clinically to prevent rhesus-negative (Rh-) women from becoming immunized against Rh+ erythrocytes from their fetuses. The suppressive mechanism is poorly understood, but it has been proposed that IgG/erythrocyte complexes bind to the inhibitory Fc receptor for IgG (FcgammaRIIB) on the B cell surface, thereby triggering negative signals that turn off the B cell. We show that IgG induces the same degree of suppression of the response to sheep erythrocytes in animals lacking the known IgG-binding receptors FcgammaRIIB, FcgammaRI + III, FcgammaRI + IIB + III, and FcRn (the neonatal Fc receptor) as in wild-type animals. Reinvestigation of the ability of F(ab')2 fragments to suppress antibody responses demonstrated that they were nearly as efficient as intact IgG. In addition, monoclonal IgE also was shown to be suppressive. These findings suggest that IgG inhibits antibody responses through Fc-independent mechanisms, most likely by masking of antigenic epitopes, thereby preventing B cells from binding and responding to antigen. In agreement with this, we show that T cell priming is not abolished by passively administered IgG. The results have implications for the understanding of in vivo regulation of antibody responses and Rh prophylaxis. (+info)
Tolerance to antigen-presenting cell-depleted islet allografts is CD4 T cell dependent.
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Pretreatment of pancreatic islets in 95% oxygen culture depletes graft-associated APCs and leads to indefinite allograft acceptance in immunocompetent recipients. As such, the APC-depleted allograft represents a model of peripheral alloantigen presentation in the absence of donor-derived costimulation. Over time, a state of donor-specific tolerance develops in which recipients are resistant to donor APC-induced graft rejection. Thus, persistence of the graft is sufficient to induce tolerance independent of other immune interventions. Donor-specific tolerance could be adoptively transferred to immune-deficient SCID recipient mice transplanted with fresh immunogenic islet allografts, indicating that the original recipient was not simply "ignorant" of donor antigens. Interestingly, despite the fact that the original islet allograft presented only MHC class I alloantigens, CD8+ T cells obtained from tolerant animals readily collaborated with naive CD4+ T cells to reject donor-type islet grafts. Conversely, tolerant CD4+ T cells failed to collaborate effectively with naive CD8+ T cells for the rejection of donor-type grafts. In conclusion, the MHC class I+, II- islet allograft paradoxically leads to a change in the donor-reactive CD4 T cell subset and not in the CD8 subset. We hypothesize that the tolerant state is not due to direct class I alloantigen presentation to CD8 T cells but, rather, occurs via the indirect pathway of donor Ag presentation to CD4 T cells in the context of host MHC class II molecules. (+info)
Mucosal immunity to influenza without IgA: an IgA knockout mouse model.
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IgA knockout mice (IgA-/-) were generated by gene targeting and were used to determine the role of IgA in protection against mucosal infection by influenza and the value of immunization for preferential induction of secretory IgA. Aerosol challenge of naive IgA-/- mice and their wild-type IgA+/+ littermates with sublethal and lethal doses of influenza virus resulted in similar levels of pulmonary virus infection and mortality. Intranasal and i.p. immunization with influenza vaccine plus cholera toxin/cholera toxin B induced significant mucosal and serum influenza hemagglutinin-specific IgA Abs in IgA+/+ (but not IgA-/-) mice as well as IgG and IgM Abs in both IgA-/- and IgA+/+ mice; both exhibited similar levels of pulmonary and nasal virus replication and mortality following a lethal influenza virus challenge. Monoclonal anti-hemagglutinin IgG1, IgG2a, IgM, and polymeric IgA Abs were equally effective in preventing influenza virus infection in IgA-/- mice. These results indicate that IgA is not required for prevention of influenza virus infection and disease. Indeed, while mucosal immunization for selective induction of IgA against influenza may constitute a useful approach for control of influenza and other respiratory viral infections, strategies that stimulate other Igs in addition may be more desirable. (+info)