The T-cell growth factors interleukin 2 (IL-2) and interleukin 7 (IL-7) induce lymphokine-activated killer (LAK) cell activity in short-term cultures of human peripheral blood mononuclear cells. Interleukin 4 (IL-4), another T-cell growth factor, induces LAK cell activity in IL-2-prestimulated lymphocytes only and inhibits LAK cell generation in normal peripheral blood mononuclear cells. Our studies of the processes involved using 21-mer phosphorothioate antisense oligonucleotides to the sequence adjacent to the start codon of IL-2 mRNA or IL-4 mRNA (effective concentration, 5 to 10 mumol/L) and cyclosporine (0.01 to 1.0 microgram/mL) or FK506 (0.01 to 1.0 ng/mL) demonstrate that IL-7-induced LAK cell activity is independent of IL-2 production and is regulated by endogenously generated IL-4. Like IL-2, IL-7 stimulated production of tumor necrosis factor alpha, but we failed to detect interferon gamma in IL-7-stimulated cultures. The implication of this regulatory feedback in IL-7-induced LAK cell generation for clinical applications is discussed.
Mice carrying the nude mutation (nu/nu) lack a functioning thymus and do not contain detectable levels of immunocompetent T cells. We now report that nu/nu mice to have lymphocytes which can be activated in vivo by heterologous erythrocytes and a Lyt-1 T cell-derived factor (interleukin 2) to generate T helper cells. Thus, a lymphokine is described which is able to restore in vivo T helper cell immunocompetence of nu/nu mice. The data may suggest that nu/nu mice contain a low number of T lymphocytes influenced by the cystic remnant of the nu/nu thymus anlage. Alternatively, the data imply that interleukin 2 circumvents the requirement of a thymus during ontogeny of T lymphocytes.
In the present study, 28 hemophiliacs substituted continuously and 5 hemophiliacs who had received almost no blood products were investigated. Cells of OKT 3+, OKT 4+, and OKT 8+ subsets were counted. Percoll separated fractions of peripheral blood mononuclear cells were examined by morphological criteria and were tested for NK cell activity. We found that the NK cell activity of both groups of hemophiliacs was decreased on testing Ficoll separated cells or low density Percoll separated cells. Normal NK cell activity was found in medium density cells of hemophiliacs. Two possible explanations are discussed: first, the NK cell activity may be suppressed in hemophiliacs and secondly, there may be a block in maturation of NK cell activity. It is unlikely that chronic substitution by blood products counts for these alterations. The possible role of chronic infections is discussed.
The clinical, immunological, and serological status of 28 patients with hemophilia A and of 13 patients with hemophilia B was investigated. Thirty-four patients were treated regularly by clotting factor concentrates and 7 patients had been substituted only 1 to 4 times. Almost all patients with severe hemophilia suffered from hepatopathy. No patient had clinical evidence of the acquired immunodeficiency syndrome (AIDS). Asymptomatic hemophiliacs showed a decreased number of T-helper (OKT 4) cells and an increased number of T-suppressor (OKT 8) cells, which resulted in an inversed OKT 4/OKT 8 cell ratio. Natural killer cell activity of all patients was decreased compared to controls. After culture there was no significant difference of NK cell activity between hemophiliacs and controls. This phenomena was interpreted as a possible maturation defect of NK-cells in vivo. No relationship between immunological alterations and hepatopathy, hepatitis markers, CMV antibodies, amount and source of required factor concentrates, and the kind of hemophilia was observed. IgG immunoglobulins were higher and the OKT 4/OKT 8 ratio lower in the eight patients with lymphadenopathy than in patients without lymphadenopathy. The prevalence of antibodies to human T-lymphotropic virus (HTLVIII) was measured in 35 hemophiliacs and in 25 polytransfused patients, most of whom were suffering from acute leukemia. In 8 of 35 hemophiliacs antibodies to HTLVIII virus were detected by an enzyme linked immunosorbent assay (ELISA) and confirmatory tests. All seropositive patients were treated by blood products from the United States. Eight hemophiliacs treated by factor concentrates from German donors only were seronegative. In comparison 2 of 25 examined non-hemophilia patients receiving multiple blood products from local donors were seropositive for HTLVIII. The results show that hemophilia patients treated by imported clotting factor concentrates have a high risk of HTLVIII positivity. Hemophiliacs substituted by blood products obtained by local donor pools have only a small risk of infection. Because non-hemophiliac polytransfused patients had HTLVIII antibodies, there must be asymptomatic virus carriers in the local donor pool. The HTLVIII antibody screening of all donors and the heat treating of factor concentrates will give better therapeutic safety.
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