thymalfasin and Acquired-Immunodeficiency-Syndrome

Thymosin α1 (Tα1) is an immunostimulatory peptide that is commonly used as an immune enhancer in viral infectious diseases such as hepatitis B, hepatitis C, and acquired immune deficiency syndrome (AIDS). Tα1 can influence the functions of immune cells, such as T cells, B cells, macrophages, and natural killer cells, by interacting with various Toll-like receptors (TLRs). Generally, Tα1 can bind to TLR3/4/9 and activate downstream IRF3 and NF-κB signal pathways, thus promoting the proliferation and activation of target immune cells. Moreover, TLR2 and TLR7 are also associated with Tα1. TLR2/NF-κB, TLR2/p38MAPK, or TLR7/MyD88 signaling pathways are activated by Tα1 to promote the production of various cytokines, thereby enhancing the innate and adaptive immune responses. At present, there are many reports on the clinical application and pharmacological research of Tα1, but there is no systematic review to analyze its exact clinical efficacy in these viral infectious diseases via its modulation of immune function. This review offers an overview and discussion of the characteristics of Tα1, its immunomodulatory properties, the molecular mechanisms underlying its therapeutic effects, and its clinical applications in antiviral therapy.

Topics: Acquired Immunodeficiency Syndrome; Humans; NF-kappa B; Thymalfasin; Thymosin; Toll-Like Receptor 2; Toll-Like Receptor 7

Thymosin alpha1 (Talpha1), first described and characterized by Allan Goldstein in 1972, is used worldwide for the treatment of some immunodeficiencies, malignancies, and infections. Although Talpha1 has shown a variety of effects on cells and pathways of the immune system, its central role in modulating dendritic cell (DC) function has only recently been appreciated. As DCs have the ability to sense infection and tissue stress and to translate collectively this information into an appropriate immune response, an action on DCs would predict a central role for Talpha1 in inducing different forms of immunity and tolerance. Recent results have shown that Talpha1: (a) primed DCs for antifungal Th1 resistance through Toll-like receptor (TLR)/MyD88-dependent signaling and this translated in vivo in protection against aspergillosis; (b) activated plasmacytoid DCs (pDC) via the TLR9/MyD88-dependent viral recognition, thus leading to the activation of interferon regulatory factor 7 and the promotion of the IFN-alpha/IFN-gamma-dependent effector pathway, which resulted in vivo in protection against primary murine cytomegalovirus infection; (c) induced indoleamine 2,3-dioxygenase activity in DCs, thus affecting tolerization toward self as well as microbial non-self-antigens, and this resulted in vivo in transplantation tolerance and protection from inflammatory allergy. Talpha1 is produced in vivo by cleavage of prothymosin alpha in diverse mammalian tissues. Our data qualify Talpha1 as an endogenous regulator of immune homeostasis and suggest that instructive immunotherapy with Talpha1, via DCs and tryptophan catabolism, could be at work to control inflammation, immunity, and tolerance in a variety of clinical settings.

Topics: Acquired Immunodeficiency Syndrome; Animals; Aspergillosis; Dendritic Cells; HIV Infections; Homeostasis; Humans; Hypersensitivity; Immunity, Innate; Inflammation; Mycoses; Neoplasms; Signal Transduction; Th1 Cells; Thymalfasin; Thymosin; Thymus Gland

Topics: Acquired Immunodeficiency Syndrome; Humans; Neoplasms; Thymalfasin; Thymosin

The immune systems of patients with AIDS are characterized by a profound defect in cell-mediated immunity which is predominantly due to a decrease in the number and function of the helper/inducer T lymphocytes, particularly the antigen-reactive cells. This defect is manifested primarily as decreases in delayed-type hypersensitivity reactions and decreased in vitro proliferation to soluble antigen. A variety of secondary manifestations of immunologic dysfunction occur, some of which result from a lack of effective inducer-cell function, others from the occurrence of opportunistic infections. Among these secondary phenomena are decreased cytotoxic lymphocyte responses, polyclonal B-cell activation, decreased monocyte chemotaxis, and a number of serologic abnormalities. The primary cause of this defect in the antigen-reactive helper/inducer T lymphocyte is infection with a class of T-cell tropic retroviruses known as HTLV-III or LAV. This virus is capable of selectively infecting T4 + lymphocytes and can be isolated consistently from patients with AIDS or AIDS-related conditions. Despite substantial knowledge concerning the nature of the immune defect in AIDS and its causative agent, little progress has been made in developing effective therapies for this uniformly fatal illness. Because the incidence of this disease continues to increase, and patients stricken with this illness have a median survival of two years, additional investigation in this area is greatly needed. Continued effort aimed at delineating the precise nature of the immune defect in these patients should be of value in attempting to enhance our understanding of the human immune system in both normal and disease states.

Topics: Acquired Immunodeficiency Syndrome; B-Lymphocytes; Deltaretrovirus; Humans; In Vitro Techniques; Interferons; Interleukin-2; Lymphocyte Activation; Macrophages; Monocytes; Retroviridae Infections; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Thymalfasin; Thymosin

The epithelial cells of the thymus synthesize at least 30 different polypeptides: the thymic hormones. The structure of 4 of them is well known. They are named thymosin alpha 1, thymopoietin, thymulin and thymic humoral factor. Biological functions and secretion regulation of thymic hormones are described as well as the interactions between brain, thymus and endocrine glands. Blood levels and clinical usefulness of thymic hormones are reviewed in different congenital or acquired immunodeficient states and in autoimmune diseases.

Topics: Acquired Immunodeficiency Syndrome; Autoimmune Diseases; Humans; Immunologic Deficiency Syndromes; Peptide Fragments; Thymalfasin; Thymic Factor, Circulating; Thymopentin; Thymopoietins; Thymosin; Thymus Extracts; Thymus Hormones

Topics: Acquired Immunodeficiency Syndrome; Antibodies, Viral; B-Lymphocytes; beta 2-Microglobulin; Biopterins; Candidiasis, Oral; Drug Combinations; Humans; Interferon Type I; Lymphocyte Activation; Neopterin; Pneumonia, Pneumocystis; Retroviridae; Sarcoma, Kaposi; Sulfamethoxazole; T-Lymphocytes, Regulatory; Thymalfasin; Thymosin; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

The adnormal levels of thymosin alpha 1 in acquired immunodeficiency syndrome (AIDS) patients, depressed T-cell function, thymus pathology, and the restoration of T-cell function by thymosin fraction 5 (TF5) lend support to the hypothesis that the thymus plays a central role in AIDS. The thymosin alpha 1 assay may provide a means of identifying symptomatic carriers of AIDS. This paper summarizes the current status of diagnostic studies with thymosin alpha 1 in AIDS and reports the 1st clinical trial with thymosin in subjects with AIDS-like immune dysfunction. Serum samples from intravenous drug abusers, homosexuals, and Haitians with AIDS have revealed thymosin alpha 1 levels at least 2 standard deviations from the mean of controls without AIDS. Preliminary data from a pilot study in homosexuals and hemophiliacs at high risk for AIDS suggest that the administration of TF5 may be effective in reconstituting some T-cell mediated specific immune functions, including cell-medicated lympholysis (CML) and the mixed lymphocyte response (MLR), and enhancing the lectin-induced production of T-cell growth factor. On the other hand, TF5 has failed to have any effects on the T4/T8 ratio, absolute lymphocyte counts, or natural killer cell activity.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Clinical Trials as Topic; Female; Hemophilia A; Homosexuality; Humans; Interleukin-2; Male; Middle Aged; Pilot Projects; Pneumonia, Pneumocystis; Risk; Sarcoma, Kaposi; Thymalfasin; Thymosin

Serum thymosin-alpha 1 levels as detected by radioimmunoassay (RIA) have been reported to be elevated in AIDS. We studied 143 individuals in two risk groups for AIDS (male homosexuals and haemophiliacs) for serum thymosin-alpha 1 and antibodies to HIV. RIA for thymosin-alpha 1 was performed in Dr A. Goldstein's laboratory at George Washington University, Washington DC. We found that similar proportions of seropositive and seronegative subjects within each risk group showed elevated thymosin-alpha 1 levels. Retesting after 6 months did not reveal significant increments over previous levels in seropositive subjects or in those developing HIV antibodies in the repeat samples. Thus, although elevated thymosin-alpha 1 levels might be a possible serum marker for AIDS, their association with HIV infection was not demonstrated. In addition, the male homosexuals we studied showed significantly lower thymosin-alpha 1 levels than haemophiliacs but this difference remains to be explained.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antibodies, Viral; Hemophilia A; HIV; Homosexuality; Humans; Male; Middle Aged; Risk Factors; Thymalfasin; Thymosin

An antiserum prepared against thymosin alpha 1, a hormone secreted by the thymus gland, effectively neutralized the AIDS-associated virus [HTLV-III/LAV (clone BH-10)] and blocked its replication in H9 cells. Reverse transcriptase activity and expression of the HTLV-III/LAV antigens p15 and p24 were inhibited by purified immunoglobulin G preparations of antisera to thymosin alpha 1. The antiviral activity of the antiserum was found to be due to a region of homology between thymosin alpha 1 and p17, a product of the gag gene of HTLV-III/LAV. Comparison of the primary sequences of thymosin alpha 1 and the gag protein revealed a 44% to 50% homology in an 18-amino acid region, between positions 11 and 28 on thymosin alpha 1 and 92 and 109 on the gag protein. The effectiveness of the thymosin alpha 1 antiserum and of immunoglobulin G-enriched preparations in blocking replication of HTLV-III(BH-10) in H9 cells suggests a novel approach to the development of an AIDS vaccine. A vaccine directed against the gag protein might overcome the problem of genetic drift in the envelope region of the virus and be useful against all genetic variants of HTLV-III/LAV.

Topics: Acquired Immunodeficiency Syndrome; Adult; Animals; Child; Deltaretrovirus; Gene Products, gag; Humans; Immune Sera; Immunoglobulin G; Rabbits; Retroviridae Proteins; Thymalfasin; Thymosin; Virus Replication

Twenty-five children with acquired immune deficiency syndrome (AIDS) or AIDS-related complex had a characteristic pattern of T cell deficiency. Abnormally low plasma thymulin levels preceded the development of peripheral blood T cell abnormalities. In contrast to patients with congenital T cell deficiencies, our patients had elevated serum levels of thymosin-alpha 1. Treatment with thymosin fraction 5 in three children with AIDS resulted in only transient clinical and immunologic improvement.

Topics: Acquired Immunodeficiency Syndrome; Child; Child, Preschool; Deltaretrovirus; Humans; In Vitro Techniques; Infant; T-Lymphocytes; Thymalfasin; Thymic Factor, Circulating; Thymosin; Thymus Hormones

Forty-two male homosexuals and/or hemophiliacs with depressed helper/suppressor T-cell ratios were treated with one of three different doses of thymosin fraction 5 (TF5, 30, 60, and 120 mg), or a single dose of thymosin Alpha One (TA1, 600 micrograms), by daily subcutaneous (SQ) administration for 10 weeks, followed twice weekly for 4 weeks. No major toxicity was noted for any of the preparations tested, although three subjects treated with TF5 had to discontinue therapy because of severe local skin reactions. Of the doses and preparations tested, only 60 mg TF5 was capable of significantly improving (p less than 0.02) mean T-cell lymphoproliferative responses to alloantigens (MLR) for six HTLV-III seropositive subjects who were abnormal prior to therapy. Peripheral blood lymphocytes from subjects treated with 60 mg TF5 also exhibited a transient restoration of mean mitogen-induced interleukin-2 (IL-2) production to normal. No effects were observed with any of the four treatment regimens on absolute helper T-cell numbers, NK activity, antibody titers to HTLV-III, or in the expression of a variety of surrogate markers for acquired immunodeficiency syndrome (AIDS). Four of the six seropositive subjects treated with 60 mg TF5 exhibited a return to depressed baseline MLR, after switching to twice weekly injections. With a median follow-up time of 20 months, six cases of AIDS developed. However, none of the five subjects whose MLR improved following treatment progressed to AIDS. We recommend daily subcutaneous (SQ) administration of 60 mg (40 mg/m2) TF5 for use in combined modality trials, along with drugs capable of suppressing replication of HTLV-III.

Topics: Acquired Immunodeficiency Syndrome; Antibodies, Viral; Drug Evaluation; Hemophilia A; HIV; HIV Antibodies; Homosexuality; Humans; Male; T-Lymphocytes; Thymalfasin; Thymosin

Thymosin alpha 1 and thymosin beta 4 were first isolated from thymosin fr. 5 and have demonstrated biological activities on the immune system. They are chemically distinct and differ in their immunological activity profiles. The levels of thymosin alpha 1 and thymosin beta 4 were assessed by radioimmunoassay in the same serum samples. Normal thymosin alpha 1 levels were 670 +/- 163 pg/ml for males and 652 +/- 162 pg/ml for females. Normal thymosin beta 4 levels were 974 +/- 400 ng/ml for males and 889 +/- 345 ng/ml for females. No correlation between the levels of the peptides in serum from normal donors was observed. Although many samples of serum from neonates (cord blood), homosexuals and AIDS patients had elevated levels of one or both peptides, no correlation between the two peptides was found. Of potential significance is the observation that while thymosin alpha 1 and beta 4 are elevated in many individuals with AIDS (57 and 48% respectively), the individuals with AIDS related immune dysfunctions had predominantly elevated thymosin alpha 1 (54 vs 15%). These studies suggest that serum levels of the two peptides are modulated separately and that both are of potential value in defining the risk of individuals for developing AIDS.

Topics: Acquired Immunodeficiency Syndrome; Homosexuality; Humans; Male; Radioimmunoassay; Risk; Thymalfasin; Thymosin

Growth of murine spontaneous and transplanted AKR T-cell lymphomas results in marked elevations of serum immunoreactive thymosin alpha 1. Thymosin alpha 1 is one of the peptide hormones believed to be secreted primarily by the thymic epithelium. This elevation, however, is not mediated by the thymus but rather, seems to be directly associated with the tumor cells. Growth of a B-cell lymphoma does not generate elevated immunoreactive thymosin alpha 1 in the serum, thus, a thymosin alpha 1-like peptide is selectively associated with these T-cell lymphomas. The possible relationship between expression of T-leukemia viruses and alpha 1 expression is discussed.

Topics: Acquired Immunodeficiency Syndrome; Age Factors; Animals; Deltaretrovirus; Lymphoma; Male; Mice; Mice, Inbred AKR; T-Lymphocytes; Thymalfasin; Thymosin; Thymus Gland

Immunological, hematological, and biochemical studies were done at the time of referral in 135 homosexual subjects, 28 of whom were symptom free (SF), 74 of whom had the acquired immune deficiency syndrome (AIDS)-related symptom complex (ARC), and 33 of whom had AIDS with Kaposi's sarcoma, opportunistic infection, or both. Of 38 laboratory parameters, 11 were significantly different than controls in the SF patients, 19 in the ARC patients, and 20 in the AIDS patients. In SF patients, delayed hypersensitivity was significantly suppressed for 6 of 12 recall antigens. In addition, the percentage of circulating lymphocytes, the percentage of T3+ cells, the percentage and absolute number of T4+ cells, the T4/T8 ratio, the blastogenic responses to phytohemagglutinin, pokeweed mitogen, and concanavalin A were depressed significantly in this group. In contrast, the percentage and absolute granulocyte count, the serum lysozyme, and the serum thymosin alpha 1 were significantly elevated in these patients. In patients with more advanced disease (ARC and AIDS), immunological and hematological parameters tended to worsen. Thus, in the AIDS patients the white blood cell count, percentage, and absolute T11+ cells, absolute T3+ cells, percentage of T4+ cells and absolute level of B-cells, as well as the monocyte adherence and delayed hypersensitivity responses to 12 of 12 recall antigens were depressed. Serum levels of thymosin alpha 1 were equally elevated in all three groups. Serum interferon was found in 15 of 18 opportunistic infection patients with or without Kaposi's sarcoma, in 3 of 9 Kaposi's sarcoma patients without opportunistic infection, but in none of the ARC or SF patients. This study has demonstrated that SF sexually active homosexuals have a characteristic pattern of immune deficiency and that immunodeficiency worsens as one compares SF to ARC to AIDS patients. The study has provided a data base for the development of prognostic criteria and for characterization and evaluation of immunorestorative and immunomodulatory therapy.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antigens, Surface; Cytotoxicity, Immunologic; Female; Homosexuality; Humans; Hypersensitivity, Delayed; Immunity; Interferons; Leukocyte Count; Leukocytes; Life Style; Lymphocyte Activation; Male; Reference Values; Rosette Formation; Sarcoma, Kaposi; Thymalfasin; Thymosin

Recently, antibodies to human T-cell leukemia virus membrane antigens (HTLV-MA) and elevated levels of beta 2-microglobulin and thymosin alpha 1 have been found with high frequency in patients with the acquired immunodeficiency syndrome. Prospective studies of asymptomatic persons at high risk for this syndrome will ascertain whether any of these findings is a predictive marker for the disease. In this study, antibodies to HTLV-MA, beta 2-microglobulin levels, and thymosin alpha 1 levels were determined for a group of asymptomatic adult hemophiliacs and their wives. Five of thirty-nine hemophiliacs had HTLV-MA antibody, compared with none of 21 wives tested. The mean beta 2-microglobulin level for hemophiliacs was significantly higher than the control value (p less than 0.001), whereas the wives had a normal mean value. The mean thymosin alpha 1 values were normal for hemophiliacs and their wives; however, 3 of 22 hemophiliacs and 1 of 16 wives had abnormally high levels. Whether any of these abnormalities correlate with subsequent development of the acquired immunodeficiency syndrome will be ascertained by longitudinal follow-up of this population.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Antibodies, Viral; beta 2-Microglobulin; Blood Coagulation Factors; Deltaretrovirus; Factor VIII; Female; Fibrinogen; Hemophilia A; Humans; Leukemia, Lymphoid; Male; Marriage; Middle Aged; Plasma; Thymalfasin; Thymosin

Topics: Acquired Immunodeficiency Syndrome; Antibodies, Viral; Cytomegalovirus; Denmark; Homosexuality; Humans; Leukocyte Count; Life Style; Male; Semen; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Thymalfasin; Thymosin; United States

Topics: Acquired Immunodeficiency Syndrome; Homosexuality; Humans; Male; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Thymalfasin; Thymosin; Thymus Hormones