Microbicidal activity of monocyte derived macrophages in AIDS and related disorders.

We have examined the ability of monocyte-derived macrophages from patients with AIDS and other HIV-related disorders to kill the intracellular pathogen Toxoplasma gondii. We have also examined the capacity of peripheral blood mononuclear cells from these patients to produce macrophage-activating and other lymphokines. The capacity to produce interleukin 2 and gamma interferon decreases from controls through asymptomatic seropositive subjects and lymphadenopathy groups A (benign) and B (prodromal) to AIDS. The decrease did not correlate precisely with the decrease in CD4+ cells in these patients. Monocyte-derived macrophages from asymptomatic HIV-infected subjects and lymphadenopathy patients showed a decreased ability to kill T. gondii after activation with recombinant gamma interferon; paradoxically, this was most striking for PGL group A. The defect was largely overcome by using Concanavalin A stimulated autologous supernatants. It was notable that macrophages from AIDS patients showed normal killing with recombinant gamma interferon, but that the supernatants from AIDS patients had reduced activity with normal macrophages. These studies confirm that functional defects of both lymphocytes and macrophages are found in HIV-infected subjects; they serve to emphasize the heterogeneity of the clinical and biological responses to this retrovirus, responses which have important implications in the pathogenesis and treatment of the immunodeficiency.

Three-year prospective study of HTLV-III/LAV infection in homosexual men.

170 symptom-free homosexual men were recruited in London in 1982-83 and 133 were evaluable in 1983-85. Of the 33 who were seropositive to HTLV-III/LAV at entry, 4 (12%) progressed to AIDS, 16 (48%) progressed to persistent generalised lymphadenopathy (PGL), and 13 (40%) remained symptom-free. A further 15 men seroconverted during the study (7% per annum), of whom 8 progressed to PGL. Serial estimations of T lymphocyte subsets showed progressive reduction in T4 numbers in the seropositive groups, but these indices also varied widely in the seronegative group. Counts of T4 and T8 cells or T4/T8 ratio at entry were not of prognostic value. Seronegative subjects were as likely as seropositives to have abnormal immunological tests. Serial measurement of T lymphocyte subsets seems to be of little prognostic or clinical value in the monitoring of populations infected with the HTLV-III/LAV virus. The strongest association with prognosis was an episode of sexually transmitted disease in the six months before entry to the study. This supports the hypothesis that intercurrent infection may be an important co-factor in the acquisition of HTLV-III/LAV infection, and in subsequent disease progression.

Studies of cellular immunity in male homosexuals in London.

97 symptom-free homosexuals were studied clinically, serologically, and with in-vivo and in-vitro tests of cellular immune function in the context of the acquired immunodeficiency syndrome (AIDS). A high proportion of these men showed abnormalities: lymphopenia (33%), decreased T-helper/T-suppressor (Th/Ts) cell ratios (43%), both these abnormalities (12%), decreased total T-helper cells (15%), monocyte chemotactic (10%) and phagocytic (27%) defects, anergy to three recall antigens (32%), and anergy to purified protein derivative despite BCG inoculation (55%). The lymphocyte abnormalities and anergy characteristic of AIDS were seen in 5%. No clear clinical or serological associations were seen for the AIDS-like defects. Trends of association were seen between higher lymphocyte counts, lower Th/Ts ratios, more T-suppressor cells and serological evidence of previous virus infection. The combination of lymphocyte abnormalities and anergy observed in these symptom-free homosexuals may represent a latent phase of AIDS.

Defective monocyte function in pyoderma gangrenosum with IgG kappa paraproteinaemia.

Peripheral blood monocytes from a patient with pyoderma gangrenosum and paraproteinaemia showed defective phagocytosis; longitudinal observations demonstrated an association between the defect, the level of paraprotein and the clinical activity of the pyoderma. Treatment with Melphalan led to a reduction in the paraprotein level and remission of the pyoderma and was accompanied by normalization of monocyte function. After 8 months remission the paraprotein level rose again and was accompanied by a recurrence of the monocyte defect; shortly after this the pyoderma recurred. Pre-incubation of normal monocytes with the patient's plasma or immunoglobulin fractions revealed that a similar defect could be induced in normal cells by the patient's monomeric IgG. The patient's serum also had anti-heparin activity and the relationship between this and the phagocytic defect was explored. These studies indicate a possible pathogenetic mechanism underlying the association between pyoderma gangrenosum and monoclonal gammopathy.