Inhibited Autoantibody Production Research Articles

Suppressor of cytokine signalling 3 (SOCS3) expressed in podocytes attenuates glomerulonephritis and suppresses autoantibody production in an imiquimod-induced lupus model

ObjectiveRecently, podocytes have been recognised not only as a physical barrier to prevent urinary protein loss but also as producers of proinflammatory cytokines. However, the roles of podocytes in the...

Allergy inhibitory receptor-1 inhibits autoantibody production via upregulation of apoptotic debris clearance by macrophages.

Allergy inhibitory receptor-1 (Allergin-1) is a newly identified immune regulatory molecule thought to influence autoantibody production. Autoantibody production, like that observed in Allergin-1-deficient mice, is crucial in the pathogenesis of several autoimmune diseases such as systemic lupus erythematosus. The purpose of this study is to clarify the regulatory role of Allergin-1-mediated autoantibody production using a murine model of thymocytic anaphylaxis. C57BL/6 (WT) and Allergin-1-deficient mice were treated with apoptotic cells from naive thymocytes stimulated by dexamethasone. Antibody titers of total or immunoglobulin G (IgG) subclass of anti-double-stranded DNA (anti-dsDNA) and anti-histone antibody from serum were measured using an enzyme-linked immunosorbent assay. Macrophages from wild-type (WT) or Allergin-1-deficient mice were co-cultured with fluorescence-labeled apoptotic thymocytes or fluorogenic reagent and resultant phagocytic activity was quantified by with flow cytometry. After apoptotic cells injection, antibody titers of total and IgG3 anti-dsDNA and total anti-histone from serum were significantly increased in Allergin-1-deficient versus WT mice. Phagocytic activity was significantly lower in macrophages from Allergin-1-deficient mice versus WT mice. Allergin-1 might play an inhibitory role in autoantibody production via upregulation of macrophage phagocytosis.

IL10 restrains autoreactive B cells in transgenic mice expressing inactive RAG1

IL10 plays a dual role in supporting humoral immunity and inhibiting inflammatory conditions. B cells producing IL10 are thought to play a key regulatory role in maintaining self-tolerance and suppressing excessive inflammation during autoimmune and infectious diseases, primarily by inhibiting associated T cell responses. The extent to which B cells, through the provision of IL10, might function to sustain or inhibit autoantibody production is less clear. We previously described transgenic mice expressing catalytically inactive RAG1 (dnRAG1 mice), which show expansion of an IL10-compentent CD5+ B cell subset that phenotypically resembles B10 B cells, hypogammaglobulinemia, and a restricted B cell receptor repertoire with features indicative of impaired B cell receptor editing. We show here that B10-like B cells in dnRAG1 mice bind the membrane-associated autoantigen phosphatidylcholine (PtC), and that in vitro lipopolysaccharide (LPS) stimulation of dnRAG1 splenocytes induces a robust IgM response enriched in reactivity toward lupus-associated autoantigens. This outcome was correlated with detection of sIgMhi B cell populations that were distinct from, but in addition to, sIgMint populations observed after similar treatment of wild-type splenocytes. Loss of IL10 expression in dnRAG1 mice had no significant effect on B10-like B cell expansion or the frequency of PtC+ B cells. Compared to IL10+/+ dnRAG1 mice, levels of serum IgM, but not serum IgG, were highly elevated in some naïve IL10−/− dnRAG1 mice, and was correlated with a significant increase in serum BAFF levels. Differentiation of sIgMint B cells from LPS-stimulated dnRAG1 splenocytes was enhanced by loss of IL10 expression and IL10 blockade, but was suppressed by treatment with recombinant IL10. In vitro LPS-induced differentiation and antibody production was inhibited by treatment with JAK/STAT inhibitors or a synthetic corticosteroid, independent of IL10 expression and genotype. Taken together, these data suggest that IL10 expression in dnRAG1 mice maintains suppression of IgM levels in part by inhibiting BAFF production, and that regulatory B10-like B cells, through the provision of IL10, constrains B cell differentiation in response to mitogenic stimuli. Furthermore, autoantibody profiling raises a possible link between CD5+ B cell expansion, mitogenic stimulation, and autoantibodies associated with autoimmune complications observed in lupus and lupus-related disorders.

Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways.

CD40/CD40L interactions play a critical role in immunity and autoimmunity. In this study, we sought to understand the requirement for CD40 signaling in the programmed cell death-1 (PD-1) checkpoint and CD28 costimulatory pathways important for maintenance of peripheral tolerance. Blocking either pathway can result in loss of self-tolerance and development of autoimmunity. We found that primary Sjögren’s syndrome (pSS) and autoimmune thyroid diseases (ATDs) that develop spontaneously in CD28-deficient IFN-γ−/− NOD.H-2h4 (CD28−/−) mice required CD40 signaling. Specifically, blockade of CD40L with the anti-CD40L mAb, MR1, inhibited autoantibody production and inflammation in thyroid and salivary gland target tissues. Unexpectedly, however, ATD and pSS in PD-1–deficient IFN-γ−/− NOD.H-2h4 (PD-1−/−) mice developed independently of CD40/CD40L interactions. Treatment with MR1 had no effect and even exacerbated disease development in pSS and ATD, respectively. Most interesting, anti-thyroglobulin and pSS-associated autoantibodies were increased following anti-CD40L treatment, even though MR1 effectively inhibited the spontaneous splenic germinal centers that form in PD-1–deficient mice. Importantly, blockade of the PD-1 pathway by administration of anti–PD-1 mAb in CD28−/− mice recapitulated the PD-1−/− phenotype, significantly impacting the ability of MR1 to suppress ATD and pSS in these mice. These results indicate that there can be different pathways and requirements to autoimmune pathogenesis depending on the availability of specific checkpoint and costimulatory receptors, and an intact PD-1 pathway is apparently required for inhibition of autoimmunity by anti-CD40L.

RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus.

ABSTRACTDuring the development of autoimmune disease, a switch occurs in the antibody repertoire of B cells so that the production of pathogenic rather than non-pathogenic autoantibodies is enabled. However, there is limited knowledge concerning how this pivotal step occurs. Here, we present genetic and pharmacological evidence of a positive modifier function for the vesicular small GTPase RhoB in specifically mediating the generation of pathogenic autoantibodies and disease progression in the K/BxN preclinical mouse model of inflammatory arthritis. Genetic deletion of RhoB abolished the production of pathogenic autoantibodies and ablated joint inflammation in the model. Similarly, administration of a novel RhoB-targeted monoclonal antibody was sufficient to ablate autoantibody production and joint inflammation. In the MRL/lpr mouse model of systemic lupus erythematosus (SLE), another established preclinical model of autoimmune disease associated with autoantibody production, administration of the anti-RhoB antibody also reduced serum levels of anti-dsDNA antibodies. Notably, the therapeutic effects of RhoB blockade reflected a selective deficiency in response to self-antigens, insofar as RhoB-deficient mice and mice treated with anti-RhoB immunoglobulin (Ig) both mounted comparable productive antibody responses after immunization with a model foreign antigen. Overall, our results highlight a newly identified function for RhoB in supporting the specific production of pathogenic autoantibodies, and offer a preclinical proof of concept for use of anti-RhoB Ig as a disease-selective therapy to treat autoimmune disorders driven by pathogenic autoantibodies.

Coumestrol inhibits autoantibody production through modulating Th1 response in experimental autoimmune thyroiditis.

Coumestrol is a common phytoestrogen found in plants and Chinese medicinal herbs. Its influences on experimental autoimmune thyroiditis (EAT) were investigated in this study. Female adult CBA/J mice were fed with drinking water containing 1% Tween80 only (Control group), 0.8 mg/l (L group) and 8 mg/l coumestrol (H group) from 6 to 15 weeks of age, respectively. Their serum coumestrol concentrations were determined by high performance liquid chromatography, which were undetectable, 43.70 ± 21.74 ng/ml and 135.07 ± 70.40 ng/ml, respectively. In addition, the mice (n = 14–16/group) were immunized twice with thyroglobulin (Tg) and Freund's adjuvant to induce EAT during the meantime. Although no overt changes in the extent of intrathyroidal mononuclear cell infiltration were shown in the two coumestrol-treated groups as compared with the controls, serum anti-Tg IgG2a, IgG3 and IgG1 titers, ratio of IgG2a to IgG1 and the percentage of T helper (Th)1 cells in the splenocytes were significantly reduced in the L group. Another consistent change was the significantly decreased expression of splenic IFN-γ mRNA after low dose of coumestrol exposure. Uterine weight was also markedly reduced in the mice of L group. These findings suggest that coumestrol treatment may have some beneficial actions against thyroid-specific autoantibody production in the development of autoimmune thyroiditis through suppression of Th1 response due to its anti-estrogenic activity.

THU0049 Uc-Mscs Inhibit Both T Cell Apoptosis and Autophagy in Patients with Systemic Lupus Erythematosus

BackgroundT cells from SLE patients have higher spontaneous apoptotic rate than that from healthy donors. The appearance of nucleosomes from these apoptotic cells in circulation may induce the production of...

MiR-210 Is Induced by Oct-2, Regulates B Cells, and Inhibits Autoantibody Production

MicroRNAs (MiRs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. In this study, we show that MiR-210 is induced by Oct-2, a key transcriptional mediator of B cell activation. Germline deletion of MiR-210 results in the development of autoantibodies from 5 mo of age. Overexpression of MiR-210 in vivo resulted in cell autonomous expansion of the B1 lineage and impaired fitness of B2 cells. Mice overexpressing MiR-210 exhibited impaired class-switched Ab responses, a finding confirmed in wild-type B cells transfected with a MiR-210 mimic. In vitro studies demonstrated defects in cellular proliferation and cell cycle entry, which were consistent with the transcriptomic analysis demonstrating downregulation of genes involved in cellular proliferation and B cell activation. These findings indicate that Oct-2 induction of MiR-210 provides a novel inhibitory mechanism for the control of B cells and autoantibody production.

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Gammaherpesvirus infections, such as those caused by EBV, have been suggested to promote the development of autoimmunity. To test this idea, we infected healthy WT and lupus-prone B6.Sle123 mice with an EBV-related and rodent-specific gammaherpesvirus, γHV68. Although acute γHV68 infection increased autoantibody levels for 4 to 6 wk, latent infection inhibited these responses for 1 y. The inhibition of autoantibody expression was only observed in B6.Sle123 females and not in males, which already displayed lower autoantibody titers. Contrary to the initial hypothesis, infection of young B6.Sle123 mice, both male and female, resulted in suppression of lymphoid activation and expansion and of glomerular inflammation and sclerosis, preserving kidney function. Moreover, γHV68 infection led to reduced autoantibody titers, lymphoid activation, and glomerular inflammation whether lupus-prone females were infected before or during disease manifestation. Finally, γHV68 infection also inhibited autoantibody production in the genetically distinct MRL/lpr lupus-prone mice. Our findings indicate that γHV68 infection strongly inhibits the development and progression of lupus-like disease in mice that spontaneously develop this condition mediating its beneficial effects at the humoral, cellular, and organ levels. The mechanisms by which the virus exerts this down-modulatory action are not yet clear, but appear to operate via reduced activation of dendritic cells, T cells, and B cells. Gammaherpesviruses coevolved with the vertebrate immune systems, establishing lifelong infections in humans and other mammals. Our findings that γHV68 infection prevents rather than exacerbates autoimmunity in mice suggest that infection with gammaherpesviruses may be protective rather than pathological in most individuals.

MS2 VLP-based delivery of microRNA-146a inhibits autoantibody production in lupus-prone mice

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of pathogenic autoantibodies. Recent studies suggest that microRNAs (miRNAs) play an essential role in immunoregulation and may be involved in the pathogenesis of SLE. Therefore, it was of interest to investigate the potential therapeutic application of miRNAs in SLE, a concept that has not been thoroughly investigated thus far. Virus-like particles (VLPs) are a type of recombinant nanoparticle enveloped by certain proteins derived from the outer coat of a virus. Herein, we describe a novel miRNA-delivery approach via bacteriophage MS2 VLPs and investigate the therapeutic effects of miR-146a, a well-studied and SLE-related miRNA, in BXSB lupus-prone mice.MethodsVLPs containing miR-146a, and the control VLPs, were prepared using an Escherichia coli expression system and then administered to lupus-prone mice over a 12-day period. We performed an enzyme-linked immunosorbent assay to evaluate the anti-dsDNA antibody, autoantibody to nuclear antigen (ANA), total IgG and total IgM levels in serum. The expression of miR-146a was analyzed by qRT-PCR. SLE-related cytokines as well as some toll-like receptor signaling pathway molecules were also measured.ResultsTreatment with MS2-miR146a VLP showed profound effects on lupus-prone BXSB mice, including an increased level of mature miR-146a, which led to a significant reduction in the expression of autoantibodies and total IgG. Remarkably, these mice also exhibited reduced levels of proinflammatorycytokines, including IFN-Interferon-α (IFN-α), Interleukin-1β (Il-1β) and Interleukin-6 (Il-6). Moreover, we showed that the toll-like receptor pathway was involved in this regulation.ConclusionRestoring the loss of miR-146a was effective in eliminating the production of autoantibodies and ameliorating SLE progression in lupus-prone mice. Thus, the induction of dysregulated miRNAs by an MS2 VLP-based delivery system may lead to novel therapies.

Invariant NKT Cells Inhibit Autoreactive B Cells in a Contact- and CD1d-Dependent Manner

Autoantibody production is a hallmark of autoimmune diseases, such as lupus and rheumatoid arthritis. Accumulating evidence suggests a role of invariant NKT (iNKT) cells in their pathogenesis. Mechanisms underlying the role of iNKT cells in these diseases, however, remain unclear. In this study, we show that iNKT cells suppress IgG anti-DNA Ab and rheumatoid factor production and reduce IL-10-secreting B cells in a contact-dependent manner, but increase total IgG production and enhance activation markers on B cells via soluble factors. In vivo reconstitution with iNKT cells also reduces autoantibody production in iNKT-deficient mice and in SCID mice implanted with B cells. Using an anti-DNA transgenic model, we found that autoreactive B cells spontaneously produce IL-10 and are activated in vivo. In the presence of activated iNKT cells, these autoreactive B cells are selectively reduced, whereas nonautoreactive B cells are markedly activated. Because iNKTs recognize CD1d, we reasoned that CD1d might play a role in the differential regulation of autoreactive versus nonautoreactive B cells by iNKT cells. Indeed, autoreactive B cells express more CD1d than nonautoreactive B cells, and CD1d deficiency in lupus mice exacerbates autoantibody production and enhances Ab response to a self-peptide but not to a foreign peptide. Importantly, iNKT cells fail to inhibit autoantibody production by CD1d-deficient B cells. Thus, iNKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner but activate nonautoreactive B cells via cytokines. Such ability of iNKTs to suppress autoantibody production, without causing global suppression of B cells, has important implications for the development of iNKT-based therapy for autoimmune diseases.

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.

Inducible Nitric Oxide Synthase Inhibitor SD-3651 Reduces Proteinuria in MRL/lpr Mice Deficient in the NOS2 Gene

Several studies have demonstrated the effectiveness of arginine analog nitric oxide synthase (NOS) inhibitor therapy in preventing and treating murine lupus nephritis. However, MRL/MpJ-FASlpr(MRL/lpr) mice lacking afunctional NOS2 (inducible NOS...

Prevention and reversal of lupus in NZB/NZW mice by costimulatory blockade with adeno‐associated virus–mediated gene transfer

To investigate the potency of costimulatory blockade with adeno-associated virus (AAV)-mediated gene transfer in the prevention and reversal of lupus in a murine model. AAV vectors expressing CTLA-4Ig or CD40Ig were injected into NZB/NZW mice. Serum levels of transgene expression and autoantibody titers were determined by enzyme-linked immunosorbent assay. The therapeutic effects on proteinuria, renal pathologic features, and survival rate were evaluated. Splenic T cell phenotypes were analyzed by flow cytometry. The humoral immune response to a foreign antigen was also examined in treated mice. A single injection of AAV serotype 8 (AAV8)-CTLA-4Ig in neonatal NZB/NZW mice before the onset of lupus effectively delayed and inhibited autoantibody production, proteinuria, and kidney damage and prolonged their lifespan. In addition, coinjection of AAV8-CTLA-4Ig and AAV8-CD40Ig vectors into neonatal mice achieved a synergistic effect and the best efficacy. The preventive effects were attributed to suppression of CD4+ T cell activation and the transition from naive to memory T cells. Moreover, coinjection of these 2 vectors in adult mice reversed the existing autoantibody levels, suppressed the development of proteinuria, and prolonged their lifespan. The therapeutic effects were found to be dependent on the vector dose. In addition, AAV-mediated long-term gene expression did not severely suppress the host humoral response to foreign antigen. Our findings show that delivery of costimulatory inhibitor transgenes by AAV vectors could prevent and reverse lupus in this murine model, suggesting the potential of AAV-mediated gene transfer as an alternative treatment for lupus.

Induction of autoantibody production is limited in nonautoimmune mice.

Many individuals develop a single or a few brief episodes of autoimmunity from which they recover. Mechanisms that quell pathologic autoimmunity following such a breakdown of self-tolerance are not clearly understood. In this study, we show that in nonautoimmune mice, dsDNA-specific autoreactive B cells exist but remain inactive. This state of inactivation in dsDNA-specific B cells could be disrupted by autoreactive Th cells; in this case T cells that react with peptides from the V(H) region of anti-DNA Abs (hereafter called anti-V(H) T cells). Immunization with anti-DNA mAb, its gamma-chain or peptides derived from its V(H) region induced anti-V(H) Th cells, IgG anti-dsDNA Ab, and proteinuria. The breakdown of B cell tolerance in nonautoimmune mice, however, was short-lived: anti-DNA Ab and nephritis subsided despite subsequent immunizations. The recovery from autoimmunity temporally correlated with the appearance of T cells that inhibited anti-DNA Ab production. Such inhibitory T cells secreted TGFbeta; the inhibition of anti-DNA Ab production by these cells was partly abolished by anti-TGFbeta Ab. Even without immunization, nonautoimmune mice possess T cells that can inhibit autoantibody production. Thus, inhibitory T cells in nonautoimmune mice may normally inhibit T-dependent activation of autoreactive B cells and/or reverse such activation following stimulation by Th cells. The induction of such inhibitory T cells may play a role in protecting nonautoimmune mice from developing chronic autoimmunity.

Antinucleolar autoantibody induced by mercuric chloride in mice: does sodium selenite inhibit autoantibody production?

Repeated exposure of subtoxic doses of mercuric chloride (HgCl2) can induce antinucleolar autoantibodies in susceptible mice. To study the immunopathological mechanism(s), sodium selenite (Na2SeO3), which is known to reduce the toxicity of mercury, is injected simultaneously with HgCl2 into mice. Equimolar Na2SeO3 nor the same amount of Se in Na2SeO3 as Hg in HgCl2 could not reduce antinucleolar autoantibody induction by HgCl2. These results indicate that the mechanism of autoimmunity induction by HgCl2 might be independent of its toxicity.

Preferential dependence of autoantibody production in murine lupus on CD86 costimulatory molecule.

Blockade of the interactions between CD28/CTLA-4 and their ligands, CD80 (B7, B7.1)/CD86 (B70, B7.2), seems an attractive means to induce antigen-specific peripheral tolerance in organ transplantation and autoimmune disease. Recently, diversities between CD80 and CD86 in expression, regulation, and function have been reported in certain cell populations and murine experimental disease models. To investigate the possible differential role of CD80 and CD86 in the development of lupus, we treated lupus-prone NZB/W F1 mice with specific monoclonal antibodies (mAb) against CD80, CD86, or both. The treatment with a combination of anti-CD80 and CD86 mAb before the onset of lupus completely prevented autoantibody production and nephritis, and prolonged survival. Interestingly, we found that anti-CD86 mAb alone, but not anti-CD80 mAb, efficiently inhibited autoantibody production. Subclass study on IgG anti-double-stranded (ds) DNA antibody revealed that the treatment with anti-CD86 mAb almost completely inhibited both IgG1 and IgG2b, but not IgG2a production. The incomplete reduction of IgG2a anti-dsDNA antibody by anti-CD86 mAb was compensated by the addition of anti-CD80 mAb. A significant reduction of mRNA for interleukin (IL)-2, interferon-gamma, IL-4 and IL-6 was observed in mice treated with a combination of anti-CD80 and CD86 mAb or anti-CD86 mAb alone. Treatment with both mAb after the onset of lupus resulted in a significantly prolonged survival with reduction of autoantibody production. These results suggest that CD86 plays a more critical role in autoantibody production, and CD86, but not CD80, contributes to Th2-mediated Ig production. However, the blockade of both CD80 and CD86 are required for preventing the development and progression of lupus.

Interleukin 12 suppresses autoantibody production by reversing helper T-cell phenotype in hepatitis B e antigen transgenic mice.

Helper T (Th) cells are classified as Th1 or Th2 cells by virtue of cytokine secretion and function as mediators of cellular or humoral immunity, respectively. Cytokines also regulate the differentiation of Th cells. For example, interleukin (IL)-12 promotes Th1 and suppresses Th2 cell development, suggesting that IL-12 may be useful therapeutically in Th2-mediated autoimmune and allergic disorders. Therefore, the effect of systemic IL-12 treatment on in vivo autoantibody synthesis in hepatitis B e antigen (HBeAg)-expressing transgenic mice, which is dependent on self-reactive Th2 cells, was examined. Low-dose IL-12 significantly inhibited autoantibody production by shifting the Th2-mediated response toward Th1 predominance. Additionally, previous studies suggest that a predominance of HBeAg-specific Th2-type cells may contribute to chronicity in hepatitis B virus infection. Therefore, IL-12 may also prove beneficial in modulating the HBeAg-specific Th response to favor viral clearance in chronic hepatitis B virus infection.

Soluble CTLA-4 can suppress autoantibody production and elicit long term unresponsiveness in a novel transgenic model.

Activation of Ag-specific T cells often requires costimulatory signals in addition to the primary signal mediated through the TCR. The CD28-B7 interaction provides one important costimulatory signal. Previous studies have shown that a soluble CD28 homologue, CTLA4lg, binds B7 with high affinity and can inhibit CD28-B7-mediated costimulation in vitro and in vivo. In this study we examined the ability of soluble human CTLA4lg to inhibit autoantibody production in vivo. For this purpose we used a novel transgenic (Tg) model of autoantibody production. Hepatitis B eAg-expressing Tg mice can be induced to produce autoantibody to the circulating autoantigen (HBeAg) by the injection of a T cell recognition site that fails to elicit T cell tolerance in these mice. Autoimmunity in this model is quantitative because serum autoantibody and autoantigen concentration are inversely correlated and easily measurable by ELISA. In this system a single regimen of CTLA4lg treatment significantly suppressed primary autoantibody production and variably led to long term unresponsiveness. Furthermore, in vivo treatment with CTLA4lg inhibited both T cell activation and T cell-B cell interactions.

Effects of cyclosporin A on the production of experimental anti-erythrocyte autoantibodies in mice

Mice were treated with cyclosporin A (CsA) (25–100 mg/kg daily, by mouth) during the induction of autoantibodies to erythrocytes by means of injections of rat erythrocytes. A high dose of CsA inhibited autoantibody production whereas a low dose temporarily potentiated it. Cell transfer and anti-Thy 1.2 treatment indicated the presence of suppressor T cells in the spleens of immunized mice. Their formation was inhibited by treatment with high dose CsA and potentiated by low dose CsA. In the CBA/H mice used, CsA treatment after immunization had no effect on autoantibody titres.