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PubMed2001

Autoimmune inner ear disorders.

There is considerable evidence to suggest that hearing and vestibular function can be influenced by autoimmune processes. A number of systemic autoimmune disorders include hearing loss and vertigo as part of their constellation of symptoms. Although classic evidence for a specific autoimmune etiology mediated by immune response directed solely at the inner ear is elusive, it appears that autoimmune damage can also exist as an entity confined to the labyrinth. Antigenic targets of autoimmunity within the labyrinth seem to be diverse. Partly because of this, the condition is difficult to diagnose. However, autoimmune disorders of the inner ear are of special interest since they are among the few forms of hearing loss that are amenable to medical treatment. Recent progress in understanding the etiology, diagnosis and treatment of autoimmune damage to the inner ear is reviewed.

Animals↗

PubMed2000

Overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis in two cases.

The overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis is a rare condition and only few cases have been published, partly associated with ulcerative colitis, but not with Crohn's disease. We report an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome in a female patient with Crohn's disease. In addition, a second case of overlap syndrome is reported in a man without inflammatory bowel disease. A 24-year-old woman was referred with a 10-month history of diarrhoea and biochemical changes including elevated serum levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and immunoglobulin G. Enzyme linked immunosorbent assay showed that antinuclear autoantibodies were elevated. Immunofluorescence for perinuclear-staining antineutrophil cytoplasmatic antibodies was positive. Diagnostic criteria of definite autoimmune hepatitis according to the International Autoimmune Hepatitis Group were fulfilled. Liver biopsy simultaneously showed criteria of autoimmune hepatitis and primary sclerosing cholangitis. Endoscopic retrograde cholangiography demonstrated features of primary sclerosing cholangitis. Colonoscopy and colonoscopic biopsies indicated an active Crohn's disease affecting the terminal ileum and the ascending and transverse colon. Furthermore, we report the case of a 28-year-old man with known primary sclerosing cholangitis for the previous 6 years, and who developed jaundice and a marked increase of aspartate aminotransferase, alanine aminotransferase and immunoglobulin G, leading to the diagnosis of definite autoimmune hepatitis. A review of the literature revealed only 16 cases of an autoimmune hepatitis/primary sclerosing cholangitis syndrome in patients without inflammatory bowel disease or in association with ulcerative colitis. We report two additional cases, one case showing an association with Crohn's disease.

Adult↗

PubMed2003

Autoimmune hepatitis, cryoglobulinaemia and untreated coeliac disease: a case report.

The clinical presentation of adult coeliac disease is often uncharacteristic, with extraintestinal symptoms being the main findings. We report a 48-year-old woman who presented with type II, hepatitis-C-negative cryoglobulinaemia, elevated liver enzymes, and iron deficiency. Antinuclear antibodies were positive, and immunoglobulin G (IgG) levels were elevated. On liver biopsy, a diagnosis of type I autoimmune hepatitis with a possible autoimmune cholangitis overlap syndrome was made. Immunosuppressive treatment led to a normalization of transaminase levels and resolved the cryoglobulinaemic vasculitis. In addition, the patient exhibited low ferritin and iron levels, which led to the diagnosis of coeliac disease. Long-standing, untreated coeliac disease is recognized to be a trigger for autoimmune disorders and is known to be associated with other autoimmune diseases, but the association with autoimmune hepatitis or autoimmune cholangitis is reported rarely. We conclude that in patients with autoimmune liver disease and unspecific clinical signs, such as iron deficiency, coeliac disease must be ruled out.

Anti-Inflammatory Agents↗

PubMed2001

Treatment of autoimmune hemolytic anemias.

Treatment of autoimmune hemolytic anemias varies depending on whether the patient has autoimmune hemolytic anemia of warm antibody type, cold agglutinin syndrome, paroxysmal cold hemoglobinuria, or autoimmune hemolytic anemia secondary to an underlying disorder. Initial therapy for warm antibody autoimmune hemolytic anemia should be corticosteroids, such as prednisone at conventional doses of 1 to 1.5 mg/kg/d orally. Criteria must be established to determine whether the therapeutic response is adequate, because long-term therapy may lead to significant detrimental side effects. Splenectomy has the advantage over therapeutic options in that it has the potential for complete and long-term remission. The major adverse effect is the syndrome of overwhelming postsplenectomy infection. Other therapeutic options, which are less likely to have long-term benefit, are immunosuppressive drugs, danazol, intravenous immunoglobulin, and plasma exchange. Therapy of cold agglutinin syndrome often is unsatisfactory. All patients should avoid exposure to cold, and if additional therapy is necessary, the therapies used for warm antibody autoimmune hemolytic anemia may be tried with less likelihood of response. Paroxysmal cold hemoglobinuria requires aggressive supportive therapy, generally supplemented by corticosteroids. Hemolysis usually terminates spontaneously. Patients with secondary autoimmune hemolytic anemia may be treated similarly to those with idiopathic autoimmune hemolytic anemia, and additional therapy for the underlying disorder also may result in remission of the hemolysis.

Adrenal Cortex Hormones↗

PubMed1985

The study and manipulation of experimental autoimmune disease using T lymphocyte lines.

Autoimmune diseases include entities of varied clinical expression such as juvenile onset diabetes mellitus, rheumatoid arthritis, multiple sclerosis, and thyroiditis. Nevertheless, these autoimmune diseases have a common origin; they are caused by clones of lymphocytes that specially attack the individual's own body components. To study autoimmune processes, we have isolated and grown as long-term cell lines the T lymphocytes that mediate several different experimental autoimmune diseases in rats or mice. These cell lines have increased our understanding of pathogenesis, but perhaps more importantly, it appears that suitably attenuated lines can be used to immunize the individual animal against its own autoimmune cells. Thus, autoimmune cells can be used as vaccines to prevent or treat the autoimmune process.

Animals↗

PubMed2005

Genetic lesions in T-cell tolerance and thresholds for autoimmunity.

The cause of common organ-specific autoimmune diseases is poorly understood because of genetic and cellular complexity in humans and animals. Recent advances in the understanding of the mechanisms of the defects underlying autoimmune disease in autoimmune polyendocrinopathy syndrome type 1 and non-obese diabetic mice suggest that failures in central tolerance play a key role in predisposition towards organ-specific autoimmunity. The lessons from such rare monogenic autoimmune disorders and well-characterized polygenic traits demonstrate how subtle quantitative trait loci can result in large changes in the susceptibility to autoimmunity. These data allow us to propose a model relating efficiency of thymic deletion to T-cell tolerance and susceptibility to autoimmunity.

Animals↗

PubMed1995

Paraneoplastic autoimmune phenomena in patients with myelodysplastic syndromes: response to immunosuppressive therapy.

We analysed the clinical features, course and response to immunosuppressive therapy in 30 patients with autoimmune disorders associated with myelodysplastic syndromes (MDS). 18 patients with MDS developed acute systemic autoimmune disorders. Common manifestations were skin vasculitis (n = 15) and arthritis (n = 11). Seven patients had an acute clinical syndrome of vasculitic skin rash, fever and arthritis with peripheral oedema in three and pulmonary infiltrates in five of these seven patients. Other acute manifestations included pericarditis, pleural effusions, skin ulceration, seizures, myositis and peripheral neuropathy. Chronic or isolated autoimmune manifestations (n = 11) included glomerulonephritis, polyneuropathy, pyoderma gangrenosum, ulcerative colitis and polyarthritis. Classic connective tissue disorders recognized included relapsing polychondritis, polymyalgia rheumatica, Raynaud's syndrome and Sjögren's syndrome. Autoimmune manifestations responded to immunosuppressive therapy (primarily prednisone) in 26/27 patients treated. Furthermore, cytopenias improved substantially in six patients, including complete normalization of peripheral blood counts in two patients with cytogenetic remission in one. Patients with a haematological response to immunosuppressive therapy had improved survival compared with non-responding patients. The autoimmune syndrome was implicated as a primary cause of death in 8/17 patients who died. Autoimmune manifestations may be more common than previously recognized in patients with MDS. Aggressive therapy with immunosuppressive agents in selected patients often controls autoimmune phenomena associated with MDS and may lead to haematological responses in some patients.

Adolescent↗

PubMed1993

Premature ovarian failure: autoimmunity and natural history.

OBJECTIVE: We studied the association of clinical and latent autoimmune diseases with circulating steroid-producing cells autoantibodies (SCA) in patients with premature ovarian failure (Group I). We investigated the presence of SCA in patients with organ-specific autoimmune diseases but without hypogonadism (Group II). We assessed whether SCA can be considered markers of hypergonadotrophic hypogonadism. DESIGN: In Groups I and II blood samples were taken at diagnosis. In a subset of patients with SCA without hypogonadism blood samples were taken at least yearly for 6 years for immunological and functional tests. PATIENTS: Group I included 50 females, aged 16-39 years; Group II included 3677 patients, aged 6-79 years, divided into Subgroup IIA (99 with Addison's disease alone or associated with other endocrinopathies or with hypoparathyroidism) and Subgroup IIB (3578 with insulin-dependent diabetes mellitus or thyroid autoimmune diseases). The follow-up group included nine subjects, aged 5-31 years (seven females and two males). MEASUREMENTS: SCA and other organ-specific autoantibodies were detected by standard indirect immunofluorescence using normal human tissues or passive haemagglutination tests. Gonadal functional tests included evaluation of FSH and LH levels by a RIA method; adrenocortical function included evaluation of cortisol and ACTH plasma levels by a RIA method. RESULTS: Three subgroups were identified in Group I on the basis of clinical autoimmune disease. 9/50 (18%) patients were found to have an Addison's disease (Subgroup IA) and in this subgroup SCA were present in 7/9 (78%); 10/50 (20%) had other autoimmune diseases (Subgroup IB) and SCA were found in 1/10 (10%); 31/50 (62%) did not have other clinical autoimmune diseases (Subgroup IC) and 1/31 (3%) had SCA. SCA were significantly increased in Subgroup IA vs IB (P = 0.017) and vs IC (P = 0.00002). In Group II, SCA were found in 20/3677 (0.5%); in particular, SCA were detected in 18/99 (18%) of the patients in Subgroup IIA and in 2/3578 (0.06%) of the patients in Subgroup IIB. The frequency of SCA in Subgroup IIA was found to be significantly increased with respect to that found in Subgroup IIB (P = 0.001 x 10(-5)). During follow-up, 3/7 females (42.8%) but 0/2 males developed hypergonadotrophic hypogonadism with a latency period of 10, 13 and 15 years, respectively. Three females and two males lacked clinical Addison's disease at the beginning of the study, but during follow-up 1/3 female and 2/2 males developed clinical Addison's disease with a mean latency period of 13 months. CONCLUSIONS: The results confirm the strong relationship between premature ovarian failure and other clinical autoimmune diseases, as well as the strong link existing between primary ovarian failure, Addison's disease and antibodies to steroid-producing cells. The study also suggests that in females antibodies to steroid-producing cells are serological markers of both potential hypergonadotrophic hypogonadism, and Addison's disease; however, in males these antibodies may be considered only as markers of potential Addison's disease.

Addison Disease↗

PubMed1994

Susceptibility to autoimmune thyroiditis in Down's syndrome is associated with the major histocompatibility class II DQA 0301 allele.

OBJECTIVE: Abnormalities of immune function, including thyroid autoimmunity, are common features of Down's syndrome, and the genetic associations of autoimmune thyroiditis have been extensively studied in otherwise normal patients with thyroid disease. In this study we have examined the HLA associations of autoimmune thyroid diseases in a cohort of adult subjects with Down's syndrome, to see whether they differed from those found in other populations. DESIGN AND MEASUREMENTS: Restriction fragment length polymorphism analysis was carried out in 41 subjects whose thyroid status was assessed by measuring thyroid function and autoantibody titres. The genotypes of subjects with and without hypothyroid autoimmune diseases were compared. SUBJECTS: Forty-one older subjects with Down's syndrome and an average age of 46.6 years under review by the Maudsley Hospital. RESULTS: Hypothyroid autoimmune disease in this study group was clearly associated with a 5.5-kb Taq1 DQA restriction fragment length polymorphism (Pc = 0.013) corresponding to the major histocompatibility (MHC) class II DQA 0301 allele. CONCLUSIONS: In contrast to Hashimoto's thyroiditis and atrophic thyroiditis, there is a strong association between class II genotypes and hypothyroid autoimmune disease in Down's syndrome. This implies a role for a gene or genes on chromosome 21 in the development of autoimmune thyroid disease.

Alleles↗

PubMed1994

Pathogenesis of Sjögren's syndrome-like autoimmune lesions in MRL/lpr mice.

Sjögren's syndrome in humans is a chronic inflammatory disease with a presumed autoimmune etiology of the exocrine organs, involving in particular the salivary and lacrimal glands. The pathogenesis of this syndrome remains unclear, but the majority of infiltrating cells in the salivary glands are CD4+ T cells both in humans and rodents. Since many cytokines are involved in the development of T cell-mediated autoimmunity, local cytokine gene expression was analyzed in vivo using an animal model for Sjögren's syndrome in MRL/lpr mice. Overexpression of interleukin-1 (IL-1)beta and tumour necrosis factor (TNF) was detected before the onset of inflammatory lesions in the salivary gland, and the upregulation of IL-6 mRNA was also found in accordance with autoimmune sialadenitis in MRL/lpr mice. The inflammatory cytokines such as IL-1 beta, TNF, and IL-6 have proved to play important roles as regulatory proteins inducing autoimmune phenomena. In addition, the expression of T cell antigen receptor beta (TCR) beta transcripts in the salivary gland tissues was analyzed. Transcript for V beta 8 was predominantly detected in the T cells infiltrating sialadenitis from the onset of the disease, suggesting that CD4+ T cells bearing TCR V beta 8 play an essential role in recognizing unknown autopeptide in the autoimmune sialadenitis of MRL/lpr mice. Furthermore, Sjögren's syndrome-like autoimmune lesions were successfully transferred into severe combined immunodeficiency (SCID) mice, and these lesions were prevented by administration of anti-CD4, and anti-V beta 8 monoclonal antibodies. This article will review recent observations of these pathogenetic analyses of autoimmune sialadenitis as it occurs in MRL/lpr mice.

Animals↗

PubMed2001

Understanding the pathogenesis of autoimmune hepatitis.

OBJECTIVES: The aim of this study was to review the pathogenic mechanisms of autoimmune hepatitis, identify gaps in knowledge, and focus future investigative efforts. METHODS: The study was based on a review of all relevant articles on the mechanisms of autoimmunity in autoimmune liver disease from 1980 to 2000, extraction of pertinent concepts from the medical literature; and integration of evolving paradigms of pathogenesis with personal experiences and investigations. RESULTS: Autoimmune hepatitis is a consequence of autoantigen exposure, genetic predisposition, and defective immunoregulatory mechanisms. Autoantigen is optimally presented by class II molecules of the major histocompatibility complex that have lysine residues at position DRbeta71 of the antigen-binding groove. Cytokines and non-disease-specific autoimmune promoters modulate immune reactivity. Cell-mediated and antibody-dependent mechanisms contribute to hepatocyte injury. CONCLUSIONS: Multiple disturbances in the homeostatic mechanisms that preserve self-tolerance are likely in autoimmune hepatitis. Future investigations must focus on individual determinants of autoantigen presentation, immunocyte activation, and liver cell destruction. Findings can then be integrated into a comprehensive knowledge base that may be applicable to other autoimmune diseases.

Autoantigens↗

PubMed1998

Are there unique autoantigens triggering autoimmune diseases?

Using three reference disease models--insulin-dependent diabetes mellitus (IDDM) as a prototype of T-cell mediated organ-specific autoimmune disease, myasthenia gravis (MG) as a prototype of autoantibody-mediated organ-specific autoimmune disease and systemic lupus erythematosus (SLE) as a prototype of non-organ-specific autoimmune disease--we have reached several conclusions: 1) All three diseases are associated with the presence of multiple autoantibodies and/or autoreactive T cells that recognize a large number of antigenic molecules. The apparent predominant role of certain antibodies in some diseases could relate to their functional properties such as acetylcholine receptor (AChR) blockade for anti-AChR autoantibodies in MG or anti-dsDNA in SLE. 2) Major target antigens are clustered in the target cell affected by organ-specific autoimmune diseases: beta cells in IDDM, striated-muscle cells in MG, or apoptotic cells in the case of SLE. 3) Antibodies and T cells recognize multiple epitopes in these molecules. 4) The most evident explanation for the observed clustering and diversity is autoantigen spreading. Spreading probably involves T cells secreting proinflammatory cytokines but also possibly antibodies as in the case of nucleosome autoantibodies in SLE. 5) The counterpart of antigen spreading is bystander suppression in which regulatory cytokines deviate the immune response towards a protective response. 6) The mechanisms underlying the initiation of the autoimmune response and antigen spreading are still undetermined. They could imply a direct abnormality of the target cell in the case of organ-specific autoimmune diseases (e.g. infection with a virus showing a selective tropism for the target cell in organ-specific autoimmune diseases, or loss of physiological regulation of major histocompatibility complex molecule expression) or could be consequence of a ubiquitous cell abnormality such as increased apoptosis in SLE. The respective roles of genetic and environmental factors in these triggering events remain to be determined.

Autoantigens↗

PubMed2004

Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases.

OBJECTIVE: To assess the tolerance and efficacy of rituximab in patients with various autoimmune diseases seen in daily rheumatological practice. METHODS: 866 rheumatology and internal medicine practitioners were contacted by e-mail to obtain the files of patients treated with rituximab for systemic autoimmune diseases. Patients with lymphoma were analysed if the evolution of the autoimmune disease could be evaluated. RESULTS: In all, 43 of 49 cases could be analysed, including 14 with rheumatoid arthritis (RA), 13 with systemic lupus erythematosus (SLE), six with primary Sjogren's syndrome (pSS), five with systemic vasculitis, and five with other autoimmune diseases. Rituximab was prescribed for lymphoma in two patients with RA and two with pSS. In the 39 other cases, rituximab was given because of the refractory character of the autoimmune disease. The mean follow up period was 8.3 months (range 2 to 26). There were 11 adverse events in 10 patients and treatment had to be discontinued in six. Efficacy was observed in 30 patients (70%): RA 11, SLE 9, pSS 5, vasculitis 2, antisynthetase syndromes 2, sarcoidosis 1. The mean decrease in corticosteroid intake was 9.5 mg/d (range 0 to 50) in responders. Seven patients experienced relapse after mean 8.1 months (5 to 15). Three patients died because of refractory autoimmune disease. CONCLUSIONS: Despite absence of marketing authorisation, rituximab is used to treat various refractory autoimmune diseases in daily rheumatological practice. This study showed good tolerance and short term clinical efficacy, with marked corticosteroid reduction in patients with SLE, pSS, vasculitis, and polymyositis.

Adult↗

PubMed2006

Autoimmune thyroid disease is associated with a diagnosis of secondary Sjögren's syndrome in familial systemic lupus.

BACKGROUND: Autoimmune thyroid disease is common in systemic lupus erythematosus (SLE). About 20% of patients with SLE have secondary Sjögren's syndrome. METHODS: Families with more than one patient with SLE were identified. All patients met the revised classification criteria, although SLE-unaffected relatives were confirmed not to satisfy these criteria. Diagnosis of autoimmune thyroid disease and Sjögren's syndrome was made on the basis of a review of medical records, interview and questionnaire administered to patients with SLE, and by a questionnaire administered to SLE-unaffected subjects. RESULTS: Of a total of 1138 patients with SLE, 169 had a diagnosis of Sjögren's syndrome. Of these 50 (29.6%) patients also had autoimmune thyroid disease. Of the 939 patients with SLE with no diagnosis of Sjögren's syndrome, 119 (12.7%) had autoimmune thyroid disease (chi2 = 20.1, p = 0.000009). There was no association of a diagnosis of hypertension with secondary Sjögren's syndrome (42% vss 47%). Among 2291 SLE-unaffected relatives, 44 had diagnosed primary Sjögren's syndrome and 16 (36.3%) of these also had autoimmune thyroid disease. 265 of 2247 (11.8%) subjects had autoimmune thyroid disease but no Sjögren's syndrome (chi2 = 24.2, p<0.001). CONCLUSIONS: Autoimmune thyroid disease is found in excess among patients with SLE with a diagnosis of secondary Sjögren's syndrome, as well as among their SLE-unaffected relatives with a diagnosis of primary Sjögren's syndrome.

Autoimmune Diseases↗

PubMed1999

HLA-B27 associated spondyloarthropathy, an autoimmune disease based on crossreactivity between bacteria and HLA-B27?

Most autoimmune diseases are associated with certain HLA types. Therefore, spondyloarthropathies (SpA) strongly associated with HLA-B27, are also often classified as autoimmune diseases. This study questions whether SpA indeed fulfils the criteria of an autoimmune disease. The Medline database was searched for all reports between 1966 and April 1998 on the presence of autoimmune reactivity in SpA patients. This search yielded 45 articles on this subject. Only eight articles study T cell reactivity. Twelve reports were found on the assessment of antibodies crossreacting between bacteria and HLA-B27. In the 45 studies demonstrating autoimmune reactions in SpA patients proper controls matched for HLA-B27, sex and age were nearly always lacking. Therefore, it is concluded that the frequency of increased autoreactivity in sera from patients and controls is not significantly different, and that this lack of autoreactivity does not justify classification of SpA as an autoimmune disease. As crossreactive antibodies against bacteria and HLA-B27 were equally present in sera from patients and controls, the pathogenetic significance of molecular mimicry between various bacteria and HLA-B27 is questionable. Furthermore, the regions of the B27 molecule that are supposed to be crossreactive with bacteria, differ in one or more amino acids among the distinct B27 subtypes. Although these differences strongly influence the binding of antibodies to the B27 molecule, there was no relation between the degree of crossreactivity of certain subtypes and the association of these subtypes with SpA. In conclusion, there is no evident proof that SpA is an autoimmune disease attributable to crossreactivity between bacteria and HLA-B27.

Antibodies, Bacterial↗

PubMed1984

Collagen autoimmune arthritis.

The evidence is now fairly conclusive that collagen-induced arthritis in rodents is mediated by antitype II collagen autoimmunity. Arthritis is probably initiated by binding of antibodies to the surface of intact articular cartilage. Many of the major manifestations of arthritis, including synovial proliferation, pannus formation, marginal erosion of bone, and destruction of cartilage, can be duplicated by injection of isolated antitype II collagen antibodies. It is not known whether delayed hypersensitivity reactions to collagen can provoke similar lesions in the absence of antibody, but circumstantial evidence suggests they do not. Also clear is that not all anticollagen antibodies are capable of inducing arthritis. The minimal requirements for arthritogenic potential are currently under investigation but probably include the ability to bind native autologous type II collagen. Also IgM antibodies alone are either ineffective or are required in relatively higher concentrations than IgG for induction of arthritis. Autoimmunity to collagen is found in many spontaneous and induced rheumatic diseases other than collagen-induced arthritis. There is at present, however, no direct evidence that this autoimmunity actually contributes to the arthritic process. Nevertheless, the human disease most often associated with collagen autoimmunity is rheumatoid arthritis. In many respects the immune reactions detected in humans with rheumatoid arthritis parallel those of arthritis in rodents. That is, responsiveness is under the control of genes within or linked to the major histocompatibility locus. High responders are limited to only a few haplotypes. Cell-mediated reactions are most vigorous in response to denatured collagen and probably have limited specificity for the type of collagen recognized. Antibodies may be separated into at least two groups, one with broad specificity for denatured collagen and a second highly specific for conformation-dependent determinants on native type II collagen. The latter antibodies are of most interest to researchers because they may be like those that induce arthritis in rodents. There is also ample evidence that antibodies are deposited in the joints of rheumatoid arthritis patients, although the specificity of these antibodies is unknown. Generally, collagen-induced arthritis is a model of antibody-initiated autoimmunity arthritis. Specifically, it is a model of type II collagen autoimmune arthritis. In consideration of its extraarticular manifestations, it may justifiably be referred to as type II collagen autoimmune disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity.

The majority of cancer antigens identified thus far have limited expression in normal tissues. It has been suggested that autoimmune disease is a necessary price for cancer immunity. This notion is supported by a recent clinical trial involving an anti-CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients. To selectively modulate cancer immunity and autoimmunity, we used anti-CTLA-4 and anti-4-1BB antibodies to treat mice with a preexisting cancer, MC38. The combination of the two antibodies led to CD8 T-cell-mediated rejection of large established MC38 tumors and long-lasting immunity to the same tumor cells, although the same regimen was not effective for B16 melanoma. More importantly, whereas individual antibodies induced inflammation and autoimmune manifestations, combination therapy increased cancer immunity while reducing autoimmunity. The reduction of autoimmune effects correlates with an increased function of regulatory T cells. Our results suggest a novel approach to simultaneously enhance cancer immunity and reduce autoimmunity.

Animals↗

PubMed1992

Lacrimal and salivary gland inflammation in the C3H/Ipr autoimmune strain mouse: a potential mode for Sjögren's syndrome.

Sjögren's syndrome is an autoimmune inflammatory disease that affects the lacrimal and salivary glands. To identify a potential animal model for study of Sjögren's syndrome, an evaluation was made of lacrimal and salivary glands in the C3H/Ipr autoimmune strain mouse at ages before (2 months) and after (5 months) systemic autoimmune disease onset at 3 to 4 months. Quantitative and qualitative analyses of C3H/Ipr lacrimal and salivary (parotid, submandibular, and sublingual) gland histopathology were performed using age-matched C3H/HeJ nonautoimmune mice to control for inflammation of nonautoimmune origin. No lacrimal or salivary gland inflammation was seen in either of the strains at 2 months of age and measures of systemic autoimmune disease were negative. At 5 months of age, the nonautoimmune C3H/HeJ controls showed a slight increase in lacrimal gland inflammation, but this was not significantly different from the 2 month old controls. A significant increase in lacrimal gland inflammation was found in the 5 month old C3H/Ipr autoimmune mice in a histologic pattern similar to that of Sjögren's syndrome in human beings. Furthermore, the degree of inflammation was positively correlated with serum immune complexes and spleen weight. Sporadic inflammation of the submandibular gland was seen in both autoimmune and control mice, but this was neither statistically significant nor correlated with measures of autoimmunity. No significant inflammation was seen in the parotid or sublingual glands.

Animals↗