thymosin and Hemophilia-A

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

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

Topics: Acquired Immunodeficiency Syndrome; Adult; Amino Acid Sequence; Antibodies, Viral; Chromatography, High Pressure Liquid; Deltaretrovirus; Hemophilia A; Homosexuality; Humans; Middle Aged; Risk; Thymosin

Amongst 160 English haemophiliacs treated with clotting factor concentrates, abnormalities of T lymphocyte subset distribution (characterized by low T4/T8 ratios and high total T8 counts), low in vitro phytohaemagglutinin stimulation and raised serum IgG levels, were more common in patients with haemophilia A than B, in patients who had received heavier blood product exposure, and in adults rather than children. A slight reduction in lymphocyte and platelet counts was found in 26% and 17% of patients. In the sample of patients tested, serum alpha 1-thymosin levels were often raised, but beta 2-microglobulin levels were usually normal. Fractionation procedures used to prepare clotting factor concentrates, and the amounts of concentrate used, are more likely to be causally related to these immunological abnormalities than the origins of source donor plasmas.

Topics: Adolescent; Adult; Aged; beta 2-Microglobulin; Blood Coagulation Factors; Child; Child, Preschool; Hemophilia A; Humans; Immunoglobulin G; Infant; Leukocyte Count; Lymphocyte Activation; Male; Middle Aged; Platelet Count; T-Lymphocytes; Thymalfasin; Thymosin

T-cell immunity and serum levels of thymosin alpha 1, beta 2-microglobulin, circulating immune complexes, serum immunoglobulin levels, antibodies to hepatitis surface or core antigen, and to cytomegalovirus, and Epstein-Barr virus were investigated in 51 patients with haemophilia A ranging in age from 2 to 52 years. All patients had received commercial U.S. lyophilized concentrates of antihaemophilic factor (AHF). The mean helper/cytotoxic-suppressor (OKT4/OKT8) ratio of 11 pre-adolescents (1.6 +/- 0.4 SE) was not significantly different from that of age matched normal controls. In contrast, the mean OKT4/OKT8 ratios of 13 adolescent (1.2 +/- 0.2 SE) and 23 adult (0.8 +/- 0.1 SE) haemophiliacs were significantly reduced. Abnormalities of lymphocyte mitogenic responses were found only in adult haemophiliacs. Nine individuals treated with commercial U.S. prothrombin complex concentrates for antibodies directed against AHF or for haemophilia B had normal mean OKT4/OKT8 values. The mean serum thymosin alpha 1 levels for each age category was similar to that of age matched controls; however, regression analysis revealed a significant relationship between elevated thymosin alpha 1 levels and decreased OKT4/OKT8 ratios in adult haemophiliacs (P = 0.012). Although the mean serum level of beta 2-microglobulin was significantly increased in the adult haemophiliac group, there was no correlation between OKT4/OKT8 ratios and any of the other serologic parameters studied.

Topics: Adolescent; Adult; Age Factors; beta 2-Microglobulin; Blood Coagulation Factors; Child; Child, Preschool; Factor VIII; Hemophilia A; Humans; Leukocyte Count; Middle Aged; T-Lymphocytes; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; 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

A 27-year-old previously healthy man with hemophilia presented with Pneumocystis carinii pneumonia. The patient had several episodes of oral candidiasis followed by disseminated infection with Mycobacterium avium-intracellulare. He was not homosexual nor did he take illicit drugs, but he had been self-administering two to four monthly infusions of factor VIII concentrate for 7 years. In-vitro lymphocyte studies showed findings consistent with the acquired immunodeficiency syndrome that had previously been reported only in homosexual men, drug addicts, and Haitian refugees. The cause of this syndrome is unknown, but the possibility that it is associated with a transmissible agent acquired through the use of blood products such as factor VIII concentrate must be considered.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antibodies, Viral; Clofazimine; Cytomegalovirus; Hemophilia A; Herpesvirus 4, Human; Humans; Immunoglobulin G; Male; Mycobacterium avium; Mycobacterium Infections; Pneumonia, Pneumocystis; Thymosin; Toxoplasma; Transfer Factor