thymosin and Lupus-Erythematosus--Systemic

Topics: Adjuvants, Immunologic; Amyloidosis; Animals; Autoimmune Diseases; B-Lymphocytes; Chronic Disease; Glomerulonephritis; Humans; Immune Complex Diseases; Interferons; Kidney Diseases; Levamisole; Lupus Erythematosus, Systemic; Mice; Rats; T-Lymphocytes; Thymosin; Transfer Factor

Pathologic and immunologic features of the spontaneous autoimmune disease of NZB and NZB/NZW F1 (B/W) mice resemble human SLE in three major respects: formation of antibodies to nucleic acids, deposition of immune complexes containing DNA in the kidney, and earlier onset of severe disease in females. Genetic, viral, and hormonal factors are involved in a pathogenetic mechanism that is manifest primarily as a disturbance in immunologic regulation. Recent studies on the sequential development of IgM and then IgG antibodies to DNA and RNA suggest that the thymus, spleen, and gonads exert important regulatory influences. We have found that sex hormones modulate the expression of autoimmunity in B/W mice, with androgens suppressing and estrogens accelerating disease. The hormones may act by restoring immunologic control.

Topics: Androgens; Anemia, Hemolytic, Autoimmune; Animals; Animals, Newborn; Antibody Formation; Antigen-Antibody Complex; Autoimmune Diseases; Castration; Disease Models, Animal; DNA; Female; Gonads; Immune Tolerance; Immunity, Cellular; Immunoglobulin G; Immunoglobulin M; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred NZB; RNA; Sex Factors; Spleen; T-Lymphocytes; Thymosin; Thymus Gland

Topics: Amyloidosis; Animals; Autoimmune Diseases; Cattle; Dogs; Endocrine Glands; Humans; Immune Adherence Reaction; Lupus Erythematosus, Systemic; Lymphocytes; Mice; Mice, Inbred CBA; Mice, Inbred NZB; Thymosin; Thymus Extracts; Thymus Gland

The important immunological activities of Thymosin alpha 1 (T alpha 1), a peptide derived from the thymus, led to its use in combination therapies in cancer patients. Prothymosin alpha (ProT alpha) is a highly acidic polypeptide, first isolated as the putative precursor of T alpha 1. However ProT alpha is now known to be more immunoreactive than T alpha 1 in certain in vivo and in vitro assays. Recent results indicate that ProT alpha may be useful to design future therapeutic interventions in cancer patients if the mechanisms underlying these effects are puzzled out. With this in mind, we radiolabeled ProT alpha to obtain a high specific activity and a high biological activity for 125I-ProT alpha. Moreover, we also obtained autoantibodies exhibiting high titers and an unique specificity for anti-ProT alpha and anti-T alpha 1. With both tools we studied the presence of binding sites for ProT alpha on the surface of lymphoblast cells. We conclude that ProT alpha binds through the non-T alpha 1 sequence.

Topics: Animals; Autoantibodies; Cattle; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Immunochemistry; Iodine Radioisotopes; Lupus Erythematosus, Systemic; Lymphocytes; Protein Precursors; Radioligand Assay; Thymosin

Autoantibodies to prothymosin alpha, an immunoactive protein that exists in a large variety of mammalian tissues, were found to be present in patients with systemic lupus erythematosus (SLE) by a new, sensitive, and specific anti-prothymosin alpha ELISA. The antigen was prothymosin alpha, purified by high-pressure liquid chromatography from goat spleen extracts. Sera from 44 SLE patients and 276 healthy individuals were screened for the presence of anti-prothymosin alpha activity; 18% of SLE sera were found to be positive, compared with 1.8% of control sera. This anti-prothymosin alpha activity appears to be idiotypically distinct from either anti-thymosin alpha 1 activity or anti-dsDNA activity, as demonstrated by inhibition experiments. Significant positive correlation exists between anti-prothymosin alpha and anti-dsDNA activities of SLE sera (r = +0.596, n = 36, P less than 0.001), while no correlation was observed with the clinical activity (X2 = 1.239, 0.1 less than P less than 0.5) or with complement levels C3 and C4.

Topics: Antibodies, Antinuclear; Autoantibodies; Autoantigens; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin Idiotypes; Lupus Erythematosus, Systemic; Protein Precursors; Thymosin

Systemic lupus erythematosus (SLE) is characterized by a variety of profound T-cell abnormalities among which are decreased autologous and allogeneic mixed lymphocyte reactions (auto-MLR and allo-MLR, respectively). In a group of 10 patients with SLE, the mean auto-MLR and allo-MLR responses, tested by tritiated thymidine incorporation, were significantly decreased. If optimal doses of highly purified prothymosin alpha (ProT alpha) were present during the auto- of allo-MLR, the T-cell proliferative responses of SLE patients were increased to normal levels. ProT alpha had more pronounced enhancing effect in patients than in normal individuals. Among patients, ProT alpha was more effective in those who had active disease and low proliferative responses. These results demonstrate that ProT alpha can fully restore the deficient T-cell proliferative responses in auto- and allo-MLR in patients with SLE. ProT alpha, or a certain peptidic fragment of it, could prove potentially useful in the treatment of SLE.

Topics: Adjuvants, Immunologic; Autoantigens; Humans; In Vitro Techniques; Isoantigens; Lupus Erythematosus, Systemic; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Protein Precursors; T-Lymphocytes; Thymosin

The blood rate of alpha 1 thymosin is increased during HIV infection, despite the thymus involution. Anti-alpha 1 thymosin antibodies inhibit HIV replication in vitro. A homology between alpha 1 thymosin and the HIV P17/18 core protein exists and would explain a cross-antigenicity. We have studied the interaction between anti P17/18 antibodies from HIV patients and alpha 1 thymosin and between an anti-alpha 1 thymosin monoclonal antibody and the P17/18 protein. We were unable to confirm any cross-reactivity. During acquired immune deficiency syndrome, a major involution of the thymus appears with a severe depletion of thymocytes and epithelial cells. Certain thymic functions are missing, as corroborated by the reduction of the hormone thymulin in the blood. At the same time, the blood rate of the 2 other hormones (partly of thymic origin), alpha 1 thymosin and beta 4 thymosin is increased. One of the theories explaining this discordance is that patients with acquired immunodeficiency syndrome produce molecules which have a cross antigenicity with these thymic hormones. Sarin et al. have recorded a 50% homology between the C-terminal part (last 18 aminoacids) of alpha 1 thymosin and the part between the 92nd and the 109th aminoacids of the HIV P17/18 protein. The cross reactivity between this P17/18 protein and alpha 1 thymosin would explain the high rates of alpha 1 thymosin found in the radio-immunoassay of sera from patients infected with HIV. Another result of this cross-reactivity is the ability of alpha 1 thymosin antibodies to inhibit HIV replication in the H9 permissive cell line.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antibodies, Monoclonal; Antibodies, Viral; Enzyme-Linked Immunosorbent Assay; HIV; HIV Antibodies; HIV Seropositivity; Humans; Lupus Erythematosus, Systemic; Reference Values; Thymosin

Topics: Amino Acid Sequence; Humans; In Vitro Techniques; Lupus Erythematosus, Systemic; Nephritis; Peptide Fragments; Rosette Formation; Thymosin

Five fragments from hexapeptide to decapeptide, corresponding to positions 16-25 of thymosin beta 9, were synthesized and their effects on low E-rosette-forming capacity with sheep erythrocytes of cells from lupus nephritis patients were compared with that of the undecapeptide (positions 16-26) of thymosin beta 9 by taking synthetic thymosin beta 9 as a standard. Two of the fragments (16-25 and 18-25) exhibited higher activity than that of the parent peptide (16-26). The other three sequences (17-25, 19-25, and 20-25) had no effect at concentrations as high as 10(-4) M.

Topics: Amino Acid Sequence; Glomerulonephritis; Humans; Immune Complex Diseases; Indicators and Reagents; Lupus Erythematosus, Systemic; Peptide Fragments; Rosette Formation; Syndrome; Thymosin

Topics: Amino Acid Sequence; Humans; In Vitro Techniques; Lupus Erythematosus, Systemic; Nephritis; T-Lymphocytes; Thymosin

Topics: Adult; Female; Humans; Lupus Erythematosus, Systemic; Myasthenia Gravis; Thymectomy; Thymosin

Topics: Arthritis, Rheumatoid; Autoimmune Diseases; Cytotoxicity, Immunologic; Humans; Lupus Erythematosus, Systemic; Lymphocyte Culture Test, Mixed; Lymphocytes; Myasthenia Gravis; Thymalfasin; Thymosin; Thymus Gland; Thymus Hormones

Five patients with autoimmune disorders were given thymosin, fraction 5, parenterally for periods ranging from 2 to 35 mth. Four patients had systemic lupus erythematosus and the 5th had rheumatoid arthritis and Sjögren's syndrome. Treatment with thymosin was based on the hypothesis of a T-suppressor defect in these autoimmune disorders. Circulating T lymphocytes increased and remained above pretreatment levels in all patients. Assays for cytotoxicity, using mouse thymocytes and patients' sera, were positive initially and declined during the course of the treatment. In all patients, serum cytotoxicity levels were reduced to zero. There has been clinical improvement in 3 patients, and in 1, the disease has become stable. The evaluation of the 5th patient has been inconclusive. No ill effects related to the administration of thymosin were observed.

Topics: Adult; Arthritis, Rheumatoid; Autoimmune Diseases; B-Lymphocytes; Complement C3; Complement C4; Female; Humans; Immunoglobulins; Lupus Erythematosus, Systemic; Middle Aged; Rosette Formation; Sjogren's Syndrome; T-Lymphocytes; Thymosin; Thymus Hormones

The possible immunomodulatory influence of thymosin on lymphocytes from patients with active systemic lupus erythematosus (SLE) has been evaluated. Such patients have decreased numbers of T-suppressor (T gamma) cells and normal numbers of T-helper (T mu) cells, resulting in an abnormally low T gamma/T mu ratio. In vitro incubation of lymphocytes from active SLE patients with thymosin resulted in a normalization of the T gamma/T mu ratio. This occurred because of a decrease in T mu cells rather than an increase in T gamma cells. The normalization of T gamma/T mu ratios in vitro in the presence of thymosin is compatible with possible in vivo immunomodulatory effects of these peptides.

Topics: Adolescent; Adult; Female; Humans; In Vitro Techniques; Lupus Erythematosus, Systemic; Lymphocyte Subsets; Male; Middle Aged; T-Lymphocytes; Thymosin

Topics: Androgens; Animals; Antibodies; Binding Sites; Cyclophosphamide; Disease Models, Animal; DNA; Female; Glomerulonephritis; Humans; Immunoglobulin G; Immunoglobulin M; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred NZB; Poly A; Thymosin

Administration of thymosin fraction V to NZB/NZW F1 mice, an animal model for human SLE, accelerated the appearance of proteinuria and anti-nDNA antibodies, increased deposition of immunoglobulins in kidneys, and significantly shortened survivals. Although the addition of thymosin to in vitro cultures of spleen and lymph node cells from thymosin-treated mice increased DNA synthesis in response to stimulation with Con A, in vivo treatment with thymosin did not affect the Con A response. There was no effect on in vitro responses to PHA or LPS, or on IgM antibody formation to SRBC (T cell dependent) or SSS III (T cell independent) immunizations. Antibodies to thymosin or contamination of our thymosin preparations with nucleic acids could not be demonstrated. The acceleration of autoimmune disease produced by thymosin treatment could not be explained by alteration of the T and B cell functions studied.

Topics: Animals; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; Cattle; Cells, Cultured; DNA; Female; Immunoglobulin M; In Vitro Techniques; Lupus Erythematosus, Systemic; Lymphoid Tissue; Mice; Mice, Inbred Strains; Mitogens; T-Lymphocytes; Thymosin; Thymus Hormones

Patients with systemic lupus erythematosus lacked suppressor T cell function. Suppressor cell activity was induced in cells from many of these patients by incubation with thymosin or cultured thymic epithelium. These results suggest that thymic manipulation may be a useful therapeutic modality in this disease.

Topics: Adolescent; Adult; Concanavalin A; Culture Techniques; Epithelium; Female; Humans; Immunotherapy; Lupus Erythematosus, Systemic; Male; Middle Aged; T-Lymphocytes; Thymosin; Thymus Gland; Thymus Hormones

Since prognosis seems to vary according to which of several possible types of disease is present, the first step is renal biopsy and histologic classification. Management options thereafter-both conventional (steroid therapy) and investigational (cytotoxic agents plus steroids, thymic hormone replacement, steroid "pulse" therapy)-are discussed in terms of recent clincal results and theoretical mechanisms of action.

Topics: Animals; Azathioprine; Cyclophosphamide; Humans; Kidney Glomerulus; Lupus Erythematosus, Systemic; Methylprednisolone; Mice; Nephritis; Prednisone; Thymosin

The in vitro effect of calf thymosin fraction 5 on T-rosette forming cells (E-RFC) was studied in Sjögren's syndrome (SS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). The baseline percent E-RFC in sixteen normal controls was67-2 +/- 6-9. E-RFC was significantly decreased in SLE (42-6 +/- 17-0, P less than 0-0001) and SS (51-8 +/- 16-9, P less than 0-002) but not in RA (59-7 +/- 14-1). Ten of twenty-five SS patients and two of eleven RA patients had less than 50% E-RFC, and all showed a significant increase after incubation with thymosin (+ 16-5 +/- 6-5%, P less than 0-0001, and + 11 +/- 4-9%, P less than 0-001, respectively). Eleven of sixteen SLE patients had less than 50% E-RFC. Their response to thymosin was less dramatic but still statistically significant (+ 5-3 +/- 6-0%, P = 0-03). There was no response to thymosin in control subjects or in patients with baseline E-RFC greater than 50%. No increase in E-RFC was seen after incubation with calf spleen fraction 5 or known stimulators of cyclic-AMP. Sera from four active SLE patients, as well as the supernatant obtained from overnight culture of the lymphocytes from one SLE patients, were able to block T-rosette formation by normal lymphocytes, even after exposure to thymosin. Two 'blocking' sera were fractionated by sucrose density gradient ultracentrifucation. In one, the blocking capacity was found to reside in the 19S region containing IgM. In the second, the blocking capacity was in the 7S region containing IgG. Four 'blocking' lupus sera were depleted of IgG or IgM by immunoabsorption with goat anti-human IgG or goat anti-human IgM sepharose 4B. The blocking ability in three sera was partially decreased by depletion of either IgG or IgM, and in a fourth, only by removing IgG. The percent of lymphocytes staining with fluorescein labelled goat anti-human immunoglobulin antisera was increased in SLE patients (35-9 +/- 20-2 vs 21-7 +/- 5-9 in controls, P = 0-02). After overnight culture, the percent of staining cells decreased to normal values. These results suggest that thymosin can stimulate the differentiation of T-lymphocytes in patients with SS, SLE, and RA when the baseline E-RFC is decreased. Furthermore, the decreased percent E-RFC in SLE is probably due to cell-bound anti-lymphocyte antibodies that block sheep erythrocyte receptors on the T-cell and, possibly, thymosin receptors on undifferentiated lymphocytes.

Topics: Adolescent; Adult; Aged; Arthritis, Rheumatoid; Binding, Competitive; Female; Humans; Immunoglobulin G; Immunoglobulin M; Immunologic Techniques; Lupus Erythematosus, Systemic; Lymphocytes; Male; Middle Aged; Receptors, Antigen, B-Cell; Sjogren's Syndrome; T-Lymphocytes; Thymosin; Thymus Hormones

Topics: Animals; Antibody Formation; Antigens; Autoimmune Diseases; B-Lymphocytes; Disease Models, Animal; DNA Replication; Histocompatibility Antigens; Humans; Immunosuppression Therapy; Lupus Erythematosus, Systemic; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred NZB; T-Lymphocytes; Thymosin; Thymus Gland; Transplantation, Homologous; Waldenstrom Macroglobulinemia

Topics: Animals; Antibodies, Antinuclear; Autoimmune Diseases; Disease Models, Animal; Lupus Erythematosus, Systemic; Mice; Serum Albumin, Bovine; Thymosin; Thymus Extracts

Topics: Age Factors; Animals; Cell Differentiation; Dogs; Humans; Immunity, Cellular; Immunologic Deficiency Syndromes; Lupus Erythematosus, Systemic; Mice; Molecular Weight; Neoplasms; T-Lymphocytes; Thymosin; Thymus Extracts