thymalfasin and Disease-Models--Animal

Thymosin alpha 1 (Ta1) is a peptide originally isolated from thymic tissue as the compound responsible for restoring immune function to thymectomized mice. Ta1 has a pleiotropic mechanism of action, affecting multiple immune cell subsets that are involved in immune suppression. Ta1 acts through Toll-like receptors in both myeloid and plasmacytoid dendritic cells, leading to activation and stimulation of signaling pathways and initiation of production of immune-related cytokines. Due to the immune stimulating effects of Ta1, the compound would be expected to show utility for treatment of immune suppression, whether related to aging or to diseases such as infection or cancer. Extensive studies in both the preclinical and clinical setting will be summarized in the subsequent sections. These studies have demonstrated improvements in immune system cell subsets and the potential of Ta1 for the treatment of a range of diseases.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Disease Models, Animal; Humans; Immunity; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Infections; Mice; Neoplasms; Thymalfasin; Thymosin; Vaccines

Topics: Aging; Animals; Atrophy; Disease Models, Animal; Female; Galactose; Mice; Mice, Inbred C57BL; Saline Solution; Thymalfasin; Thymopoietins; Thymus Gland

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding for the ion channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Long considered a lung disease for the devastating impact on the respiratory function, the recent diagnostic and therapeutic advances have shed the light on the extra-pulmonary manifestations of CF, including gastrointestinal, hepatobiliary and pancreatic symptoms. We have previously demonstrated that thymosin alpha1 (Tα1), a naturally occurring immunomodulatory peptide, displays multi-sided beneficial effects in CF that concur in ameliorating the lung inflammatory pathology. In the present study, by resorting to murine models of gut inflammation with clinical relevance for CF patients, we demonstrate that Tα1 can also have beneficial effects in extrapulmonary pathology. Specifically, Tα1 restored barrier integrity and immune homeostasis in the inflamed gut of CF mice as well as in mice with the metabolic syndrome, a disorder that may arise in CF patients with high caloric intake despite pancreatic sufficiency. The protective effects of Tα1 also extended to pancreas and liver, further emphasizing the beneficial effects of Tα1 in extra-pulmonary complications of CF. By performing wide-ranging multi-organ anti-inflammatory effects, Tα1 could potentially integrate current therapeutic approaches to tackle the complex symptomatology of CF disease.

Topics: Animals; Candida albicans; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Female; Homeostasis; Humans; Immunologic Factors; Kynurenine; Liver; Lung; Mice; Mutation; Obesity; Pancreas; Signal Transduction; Thymalfasin

Cognitive impairment is a significant sequela of traumatic brain injury (TBI) especially blast induced traumatic brain injury (bTBI), which is characterized by rapid impairments of learning and memory ability. Although several neuroprotective agents have been postulated as promising drugs for bTBI in animal studies, very few ideal therapeutic options exist to improve cognitive impairment following bTBI. Thymosin α1(Tα1), a 28-amino-acid protein that possesses immunomodulatory functions, has exhibited beneficial effects in the treatment of infectious diseases, immunodeficiency diseases and cancers. However, it remains unclear whether Tα1 has a therapeutic role in bTBI. Thus, we hypothesized that Tα1 administration could reverse the outcomes of bTBI. The blast induced TBI (bTBI) rat model was established with the compressed gas driven blast injury model system. A consecutive Tα1 therapy (in 1 ml saline, twice a day) at a dose of 200 µg/kg or normal saline (NS) (1 ml, twice a day) for 3 days or 2 weeks was performed. Utilizing our newly designed bTBI model, we investigated the beneficial effects of Tα1 therapy on rats exposed to bTBI including: cognitive functions, general histology, regulatory T (Treg) cells, edema, inflammation reactions and the expression and phosphorylation level of tau via Morris Water Maze test (MWM test), HE staining, flow cytometry, brain water content (BWC) calculation, IL-6 assay and Western blotting, respectively. Tα1 treatment seemed to reduce the 24-hour mortality, albeit with no statistical significance. Moreover, Tα1 treatment markedly improved cognitive dysfunction by decreasing the escape latency in the acquisition phase, and increasing the crossing numbers in the probe phase of MWM test. More interestingly, Tα1 significantly inhibited tau phosphorylation at the Thr205 epitope, but not at the Ser404 and Ser262 epitopes. Tα1 increased the percentage of Treg cells and inhibited plasma IL-6 production on 3d post bTBI. Moreover, Tα1 suppressed brain edema as demonstrated by decrease of BWC. However, there was a lack of obvious change in histopathology in the brain upon Tα1 treatment. This is the first study showing that Tα1 improves neurological deficits after bTBI in rats, which is potentially related to the inhibition of tau phosphorylation at the Thr205 epitope, increased Treg cells and decreased inflammatory reactions and brain edema.

Topics: Animals; Blast Injuries; Brain; Brain Injuries, Traumatic; Cognition; Cognitive Dysfunction; Disease Models, Animal; Epitopes; Hippocampus; Interleukin-6; Maze Learning; Neuroprotective Agents; Phosphorylation; Rats; tau Proteins; Thymalfasin; Treatment Outcome

Thymosin alpha 1 (Tα1) is a biological response modifier that has been introduced into markets for treating several diseases. Given the short serum half-life of Tα1 and the rapid development of Fc fusion proteins, we used genetic engineering method to construct the recombinant plasmid to express Tα1-Fc (Fc domain of human IgG4) fusion protein. A single-factor experiment was performed with different inducers of varying concentrations for different times to get the optimal condition of induced expression. Pure proteins higher than 90.3% were obtained by using 5 mM lactose for 4 h with a final production about 160.4 mg/L. The in vivo serum half-life of Tα1-Fc is 25 h, almost 13 times longer than Tα1 in mice models. Also, the long-acting protein has a stronger activity in repairing immune injury through increasing number of lymphocytes. Tα1-Fc displayed a more effective antitumor activity in the 4T1 and B16F10 tumor xenograft models by upregulating CD86 expression, secreting IFN-γ and IL-2, and increasing the number of tumor-infiltrating CD4+ T and CD8+ T cells. Our study on the novel modified Tα1 with the Fc segment provides valuable information for the development of new immunotherapy in cancer.

Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Disease Models, Animal; Disease Progression; Female; Half-Life; Humans; Hydrocortisone; Immunocompromised Host; Immunoglobulin Fc Fragments; Immunomodulation; Male; Melanoma; Melanoma, Experimental; Mice; Prognosis; Rats; Recombinant Fusion Proteins; Thymalfasin; Xenograft Model Antitumor Assays

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious CF therapy. To date, no individual drug with pleiotropic beneficial effects is available for CF. Here we report on the ability of thymosin alpha 1 (Tα1)-a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent-to rectify the multiple tissue defects in mice with CF as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology: it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 has strong potential to be an efficacious single-molecule-based therapeutic agent for CF.

Topics: Adjuvants, Immunologic; Animals; Autophagy; Blotting, Western; Cell Line; Chloride Channels; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Disease Models, Animal; Epithelial Cells; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Immunoprecipitation; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Mice; Mice, Inbred CFTR; Patch-Clamp Techniques; Protein Stability; RAW 264.7 Cells; Respiratory Mucosa; Thymalfasin; Thymosin; Ubiquitin Thiolesterase; Ubiquitination

Recent understanding of the complex pathophysiology of melanoma and severe sepsis suggests that immune-modulating compounds such as thymosin alpha 1 (INN: thymalfasin; abbreviated Ta1) could be useful in the treatment of these two unrelated immune-suppressing indications.. Three nonclinical murine models were utilized, including: i) a lung metastasis B16 model; ii) a B16-based tumor growth model; and iii) a cecal-ligation and puncture (CLP) sepsis model.. In the lung metastasis model, Ta1 treatment alone led to a 32% decrease in metastases (p < 0.05). Additionally, combinations of Ta1 and an anti-PD-1 antibody led to significantly fewer metastases than vehicle. In the tumor growth model, significant decreases in tumor growth were seen: 34% (p = 0.015) to 46% (p = 0.001) depending on the Ta1 dose. In the CLP sepsis model, Ta1 treatment showed a positive trend towards increased survival and decreased bacterial load. In this CLP model, Ta1 also appeared to have an effect on the levels of some biomarkers.. All three models demonstrated a benefit after treatment with Ta1, with no evidence of toxicity. These initial pilot studies support the hypothesis that immune-suppressive indications, including sepsis and melanoma, may be treated with Ta1 alone or by Ta1 in combination with other immunotherapies.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Immunosuppressive Agents; Lung Neoplasms; Melanoma, Experimental; Mice; Sepsis; Skin Neoplasms; Thymalfasin; Thymosin

To explore the impact of triple anti-tumor therapy based on thymosin α1 (Tα1) combined with Huaier granule(HG) and sirolimus on the level of serum alpha-fetoprotein (AFP) in rat models of liver cancer.. Ninety Sprague-Dawley rats were randomly divided into triple anti-tumor therapy group, Tα1 group, HG group, sirolimus group, positive control and blank control groups, with 15 rats in each group. Except the blank control group, the rats in the other groups were induced using diethylnitrosamine (DEN) to establish liver cancer models. After DEN treatment, the triple therapy group underwent 0.8 mg/kg Tα1 subcutaneous injection (from once a day for two weeks to twice a week since the third week), 0.35 g/kg HG gavage (three times a day) and 1 mg/kg sirolimus gavage (once a day). The dose of the rest single drug groups were the same with that of the triple therapy group. The positive control and blank control groups were not treated with the drugs. The treatment lasted 20 weeks. Then, the behavior of the rats were observed at the different time points, and the level of serum AFP in the rats were detected at 6, 16, 18, 20 weeks, respectively.. The typical symptoms of liver cancer were seen in the DEN-induced rats at 16 weeks. Since the tenth week, 6 rats died one after another. Pathological section of rat liver tissue suggested that the rat models were established successfully. According to the incidence rate of liver cancer and the survival rate at 20 weeks, the triple anti-tumor therapy was significantly superior to the single drug treatments. In addition, the triple anti-tumor therapy significantly reduced the level of serum AFP in the rats.. The triple anti-tumor therapy can significantly prolong the survival time of rats with liver cancer, decrease the cancer incidence rate and the level of serum AFP.

Topics: alpha-Fetoproteins; Animals; Antineoplastic Combined Chemotherapy Protocols; Behavior, Animal; Carcinoma, Hepatocellular; Disease Models, Animal; Liver; Liver Neoplasms; Male; Rats; Rats, Sprague-Dawley; Sirolimus; Survival Analysis; Thymalfasin; Thymosin

Immune dysfunction is a major cause of mortality in septic patients. Current evidence indicates an important role for dendritic cells (DCs) in the pathophysiology of immune dysfunction, and these cells are potential targets of immunomodulation therapies. In the present study, our aim was to enhance the resistance of endotoxemic mice to bacterial translocation and secondary infection and to improve the outcome of these infections using a combination therapy consisting of thymosin alpha1 and dexamethasone in a timely manner according to the changes of DCs' number. The effect of treatment with dexamethasone (DXM) and thymosin alpha1 (Tα1) on DCs was investigated by examining their number, MHCII and CD86 expression and their capacity to induce T cell activation. Endotoxemic mice were randomly divided into five treatment groups. The survival rates, the levels of TNF-α and IL-10, the occurrence of bacterial translocation, and the ability to clear secondary infections were determined. Additionally, the behavior of DCs over time was also evaluated. Tα1 induced significant increases in DC numbers in vivo, whereas DXM reduced cell numbers both in vitro and in vivo. However, neither drug induced significant changes in the capacity of DCs to induce T cell activation or their expression of MHCII or CD86. Among the five treatment groups, the mice treated with a combination of DXM and Tα1 had the highest survival rate; this increased survival was associated with a decrease in bacterial translocation to extra-intestinal organs and an enhanced ability to eradicate secondary infections by reversing the change in DC numbers during endotoxemia. Immunomodulatory therapy that combines Tα1 and DXM in a timely manner and was based on changes in DCs enhanced the resistance of endotoxemic mice to bacterial translocation and secondary infections, improving the outcome of the infection.

Topics: Animals; B7-2 Antigen; Bacterial Translocation; Cells, Cultured; Dendritic Cells; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Endotoxemia; Escherichia coli Infections; Female; Histocompatibility Antigens Class II; Immunologic Factors; Inflammation Mediators; Interleukin-10; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Sepsis; T-Lymphocytes; Thymalfasin; Thymosin; Time Factors; Tumor Necrosis Factor-alpha

Radiation-induced lung injure is one of the major factors of limitation in radiotherapy for lung cancer. Whether the use of thymosin and radiotherapy simultaneously would increase the radiation-induced lung injure is unclear. The aim of this study is to evaluate the effects of thymosin alpha-1 on radiation induced pneumonitis in mice.. Three groups of mice, control (C), radiation alone (RT), thymosin alpha-1 plus radiation (T+RT), were entered into the study. The weight and mortality of mice, pleural effusion, quantity of protein and cell count in the bronchoalvealar lavage (BAL) and pulmonary fibrosis score were evaluated as the outcome measures.. The mortality ratio of the T+RT and RT groups were 3/14, 2/10, respectively. The time of death were all in the 23-24 weeks after radiotherapy. There was no pleural effusion in the T+RT group other than 2/2 occurred in RT group. The quantity of protein, cell number and neutrophil number in the BAL and lung coefficient in mice of T+RT group were remarkably lower than that of RT group, but the BALF macrophages number was remarkably higher than that in RT group in the 8 weeks. The quantity of protein, cell number, neutrophil number and macrophages number in the BAL, lung coefficient, the scores of lung fibrosis in mice of T+RT group were significantly lower than that of RT group in the 24 weeks. All test data were lowest in mice of C group. And there was no obvious pulmonary fibrosis in the mice of C group.. Thymosin alpha-1 could relieve radiation-induced acute and late pulmonary injuries.

Topics: Animals; Disease Models, Animal; Female; Humans; Lung; Mice; Mice, Inbred C57BL; Radiation Pneumonitis; Thymalfasin; Thymosin; X-Rays

Tregs are involved in immune disorder during sepsis; they can lead to a Th2 immune reaction. Their inhibitory effects can help alleviate inflammatory injury, but may also cause secondary immune inhibition. Thymosin-alpha1 is a polypeptide with powerful immunomodulatory activities. Current reports have shown that Thymosin-alpha1 conferred beneficial effects to septic patients. To explore the relationship between Thymosin-alpha1 and Tregs, in this study, we investigated the changing trend in CD4(+)CD25(+)Foxp3(+) T lymphocytes in a CLP septic mouse model. We also investigated the variation of apoptotic rate of CD4(+)CD25(+) T lymphocytes, cytokine variation, and change of model survival rate when Thymosin-alpha1 intervening or not. We observed that the 72-h survival rate was improved, the percentage of CD4(+)CD25(+)Foxp3(+) T lymphocytes decreased and the apoptosis rate of CD4(+)CD25(+) T lymphocytes increased after intervention of Thymosin-alpha1. At same time the expression of pro-inflammation cytokines IL-2, TNF-alpha and anti-inflammatory cytokines IL-10 and TGF-beta were regulated. In conclusion, Thymosin-alpha1 can effectively control the inflammatory response intensity and improve the 72-h survival rate of septic mice. Regulating Tregs may be another important role of Thymosin-alpha1 conditioning the immune reaction in sepsis.

Topics: Animals; Apoptosis; Cytokines; Disease Models, Animal; Forkhead Transcription Factors; Ileum; Immunologic Factors; Mice; Sepsis; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Thymalfasin; Thymosin

After the initial dramatic effects, observed in a Lewis lung carcinoma animal model, using a combination of thymosin alpha 1 (Talpha1) and interferon (IFN) after cyclophosphamide, a number of other preclinical models in mice (Friend erythroleukemia and B16 melanoma) and in rats (DHD/K12 colorectal cancer liver metastasis) have confirmed the efficacy of the combination therapy with Talpha1 and either IFN or IL-2 plus chemotherapy. These results provided the scientific foundation for the first clinical trials using Talpha1 in combination with BRMs and/or chemotherapy. Pivotal trials in advanced non-small cell lung cancer (NSCLC) and melanoma with Talpha1 and IFN-alpha low doses after cis-platinum or dacarbazine produced the first evidence of the high potentiality of this approach in the treatment of human cancer. The combination of Talpha1 and IFN-alpha was also used in patients affected by chronic B and C hepatitis including IFN-nonresponders and infected by precore mutants or genotype 1b. Further studies demonstrated additional biological activities clarifying the mechanism of action of Talpha1, partially explaining the synergism with IFN. It has been shown the capacity of activating infected dendritic cells through Toll-like receptor signaling, thus influencing the inflammation balance, and of increasing the expression of tumor, viral, and major histocompatibility complex (MHC) I antigens. Dose-response studies suggested the possibility of improving the efficacy of this molecule reducing the overall toxic. Based on these information two clinical trials are ongoing: a large phase II on advanced melanoma patients treated with Talpha1 at different doses after dacarbazine and a phase III one, on IFN-resistant hepatitis C virus (HCV) patients treated with a triple combination (IFN, ribavirin, and Talpha1).

Topics: Animals; Antineoplastic Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Disease Models, Animal; Killer Cells, Natural; Mice; Neoplasms, Experimental; Rats; Thymalfasin; Thymosin

The aim of this study was to investigate the effect of thymosin alpha 1 (TA1) on severe acute pancreatitis (SAP) in rats.. Healthy Sprague-Dawley rats (n = 72) were randomly divided into four groups: control group, SAP group, and two TA1 treated groups. SAP was induced by injection of 5% sterile sodium taurocholate into the biliopancreatic duct (BPD), after which TA1 was given subcutaneously at 0 and 2 h at a dose of 100 microg/kg. The rats were killed at 3, 6 and 12 h, respectively. Serum amylase and lipase, interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), pancreatic wet/dry weight ratio and the percentage of CD3/CD4+/CD8+ T cells in peripheral blood mononuclear cells (PBMC) were measured. Next, 30 rats were randomly divided into three groups (each group containing 10 animals): SAP group (S) and two TA1 treated groups. The effects of TA1 on the survival of SAP were assessed 72 h after the induction of SAP.. There was no significant change in the serum amylase and lipase levels after TA1 administration. Levels of serum IL-1beta, TNF-alpha and pancreatic wet/dry weight ratio were significantly reduced after TA1-treatment. Application of TA1 significantly balanced CD3/CD4+/CD8+ T cells of PBMC and improved histological scores and the survival rate.. TA1 can reduce pancreatic inflammation by regulating differentiation of CD3/CD4+ T cells and decreasing the release of cytokines, thus attenuates pancreatic severity in SAP rats.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents; CD3 Complex; CD4 Lymphocyte Count; CD4-CD8 Ratio; Disease Models, Animal; Interleukin-1beta; Lipase; Lung; Male; Organ Size; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Severity of Illness Index; T-Lymphocytes; Taurocholic Acid; Thymalfasin; Thymosin; Time Factors; Tumor Necrosis Factor-alpha

To investigate the effect of thymosin alpha1 on immunological function and protein metabolism in peritoneal sepsis rats.. We observed the effect of thymosin alpha1 on T cell subclassification, TNFalpha, IL-6, IL-10, albumin, C-reactive protein (CRP) and mortality in cecal ligation and puncture (CLP) induced septic rats.. Concentration of TNFalpha and IL-6 in CLP induced septic rats increased significantly, and concentration of IL-10 decreased significantly compared to control group. Thymosin alpha1 significantly decreased TNFalpha, IL-6, and significantly raised concentration of plasma IL-10, percent of CD(3), CD(4), and CD(4)/CD(8) in septic group. Thymosin alpha1 reduced degressive degree of albumin. Concentration of CRP increased in both septic groups, but was less prominently in thymosin alpha1 treated group. Thymosin alpha1 reduced cumulate 7-day mortality.. Thymosin alpha1 can improve immunological function, inflammation condition and protein metabolism.

Topics: Adjuvants, Immunologic; Animals; C-Reactive Protein; Disease Models, Animal; Interleukin-10; Interleukin-6; Peritonitis; Rats; Rats, Sprague-Dawley; Sepsis; T-Lymphocyte Subsets; Thymalfasin; Thymosin; Tumor Necrosis Factor-alpha

We investigated the effects of the systemic administration of thymosin alpha 1 plus relatively low doses of human recombinant interleukin-2 or very low doses of interferon alpha,beta in untreated and cyclophosphamide (CY)-treated DBA/2 mice challenged either subcutaneously or intravenously (i.v.) with Friend erythroleukemia cells (FLC). Both treatments resulted in the complete regression of subcutaneous tumor and cured a significative percentage of mice. They also increased the survival time of mice i.v. injected with large numbers of FLC. Neither immunotherapy alone nor CY, alone or in combination with single cytokines, produced similar effects. The antitumor action of these combined chemoimmunotherapy protocols seems to involve activation of the immune response since (a) a synergistic increase of the cytotoxicity of spleen cells was demonstrated in treated mice; (b) selective in vivo depletion of asialo-GM1, CD4, or CD8-positive cells abrogated this antitumor activity; and (c) a high lymphoid cell infiltration was found at the tumor site and in the livers of treated mice.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; CD4 Antigens; CD8 Antigens; Cyclophosphamide; Cytotoxicity, Immunologic; Disease Models, Animal; Friend murine leukemia virus; G(M1) Ganglioside; Interferon-alpha; Interferon-beta; Interleukin-2; Leukemia, Erythroblastic, Acute; Leukemia, Experimental; Male; Mice; Mice, Inbred DBA; Thymalfasin; Thymosin; Tumor Virus Infections

Topics: Animals; Antiviral Agents; Disease Models, Animal; Female; Follow-Up Studies; Hepadnaviridae; Hepatitis, Viral, Animal; Male; Marmota; Thymalfasin; Thymosin

The biological basis for autoimmunity and immunoincompetence in the BB rat has yet to be localized. In spite of normal thymic histology, thymocyte subsets and blastogenesis, thymus gland products (thymosins) have yet to be studied. In the present report, thymus gland function was studied by measuring thymosin alpha 1 levels at one time point in the BB rat compared with control rates, and BB rat responses to exogenous thymosin (Thymosin fraction 5) were observed. At five months of age, BB rats had thymosin alpha 1 levels comparable to Lewis and Wistar furth rats. Thymosin fraction 5 increased the ratio of peripheral blood W3/25 positive to OX8 positive cells, but otherwise had no effect on the BB rats' T-cell immunodeficiency, or frequencies of tissue autoantibodies or insulin-dependent diabetes. Although B-lymphocyte counts were normal in BB rats, splenocyte responses to B-lymphocyte mitogens were depressed. However, thymosin fraction 5 improved the BB rat B-lymphocyte blastogenesis to near normal for Mycoplasma neurolyticum. Coupled with our previous work, our results suggest that the immune derangement in the BB rat resides outside the thymus.

Topics: Animals; Autoantibodies; Bacterial Toxins; Concanavalin A; Diabetes Mellitus, Type 1; Disease Models, Animal; Leukocytes; Lymphocyte Activation; Mycoplasma; Rats; Rats, Inbred BB; Rats, Inbred Lew; Rats, Inbred WF; Thymalfasin; Thymosin; Thymus Gland

The effects of Ta-1, a peptide constituent of thymosin fraction 5, were studied on murine autoimmune thyroiditis using two congenic strains of mice, B10.Br (Br) and B10.D2 (D2), which are sensitive and resistant to experimental autoimmune thyroiditis (EAT) induction, respectively. EAT was induced by either 2 weekly iv injections of mouse thyroglobulin with adjuvant lipopolysaccharide (LPS) or intradermal injection of thyroglobulin mixed with complete Freund's adjuvant (CFA). The criteria for induction and intensity of thyroiditis were the level of lymphoid infiltration in the thyroid gland and the titer of anti-thyroglobulin antibodies. Ta-1 was given in 5 or 10 daily sc injections in doses ranging from 0.0001 to 0.1 microgram/injection. The injections were commenced at varying intervals from the 1st to the 4th week after immunization. T-Cell subsets in the spleens were determined 2 weeks after the first antigen injection and thyroid infiltration was determined 3 weeks later. Treatment with Ta-1 between the two antigen injections increased the level of thyroiditis in resistant mice, but had no effect in sensitive mice. Treatment for the first 2 weeks had similar effects in resistant mice, but also suppressed thyroiditis in the sensitive strain. Later treatments, during the 3rd and 4th weeks after immunization also revealed immunomodulating properties of Ta-1, with a suppressing effect on thyroiditis in sensitive mice and an enhancing effect in the resistant strain. Both effects of Ta-1 were dose dependent. The effects of Ta-1 on the individual phenotypes were also dose dependent. The dose of 0.01 microgram greatly lowered the percentages of Lyt-2+3+ cells in D2 mice and mildly increased the percentages in Br mice, but did not change the Lyt-1+ cell level in either strain. On the other hand, the dose of 0.001 microgram greatly increased the percentage of Lyt-1+ cells in D2 mice and mildly decreased it in the Br strain, but did not alter the Lyt-2+3+ cell subset in either strain. Thus, both doses of Ta-1 modulated Lyt-1+/2+3+ ratios, with each dose affecting a different T-cell subset. The changes in the response to thyroglobulin are apparently exerted through the regulation of the functional T-cell subset balance.

Topics: Animals; Disease Models, Animal; Immunity, Cellular; Immunization; Mice; Mice, Inbred Strains; Spleen; T-Lymphocytes; Thymalfasin; Thymosin; Thyroiditis, Autoimmune