Harry E. Prince

Recombinant Alpha-2 Interferon Therapy for Kaposi's Sarcoma Associated with the Acquired Immunodeficiency Syndrome

In a randomized prospective study we tested the toxicity and efficacy of recombinant alpha-2 interferon in the treatment of Kaposis sarcoma associated with the acquired immunodeficiency syndrome. High doses (50 X 10(6) U/m2 body surface area, intravenously) or low doses (1 X 10(6) U/m2, subcutaneously) of recombinant alpha-2 interferon were administered to 20 patients for 5 days/wk, every other week, for four treatment cycles. Therapy was well tolerated subjectively and caused only mild hematologic and hepatic toxicity at both dose levels. No consistent or sustained changes were seen in immunologic variables during or after treatment. Six patients with Kaposis sarcoma, four at high dose and two at low dose, had objective responses (complete or partial) to treatment. However, therapy did not appear to eradicate cytomegalovirus carriage or prevent opportunistic infections related to cytomegalovirus.

Quantitative changes in T helper or T suppressor/cytotoxic lymphocyte subsets that distinguish acquired immune deficiency syndrome from other immune subset disorders

Quantitative measurements of the immune cell subgroups, T helper (Leu 3+/OKT4+) cells and T suppressor/cytotoxic (Leu 2+/OKT8+) cells, were made in patients having acquired immune deficiency syndrome (AIDS) with Kaposis sarcoma and in patients with AIDS and opportunistic infection, as well as in three other relevant populations. These included patients with lymphadenopathy syndrome, e.g., homosexually active males with lymphadenopathy who sought medical care for additional symptoms, and healthy male homosexuals, as well as a control population. Decrease in the number of T helper cells is characteristic of AIDS with Kaposis sarcoma or opportunistic infection. Augmentation of the T suppressor/cytotoxic cell population is rare in AIDS with Kaposis sarcoma but is more frequent in AIDS with opportunistic infection. Augmentation of the T suppressor/cytotoxic cell population, however, may occur in a variety of circumstances, including cytomegalovirus and other viral infections, in healthy, homosexually active males, and in otherwise healthy hemophiliac subjects receiving factor VIII treatment. Reduced T helper:T suppressor/cytotoxic cell ratio can be caused by either decrease in the number of T helper cells or augmentation of the T suppressor/cytotoxic cell population. Lowered T helper:T suppressor/cytotoxic cell ratio does not, by itself, help to distinguish between AIDS and other causes of reduced ratios. Quantitative measurements are needed to define the T subset changes. AIDS is characterized by decrease in the number of T helper cells and reduced T helper:T suppressor/cytotoxic cell ratio. The T helper (Leu 3+) and T suppressor/cytotoxic (Leu 2+) cell subpopulations can change independently. Identification of decrease in the number of T helper cells as an alteration that occurs independently of numerical change in other lymphoid subpopulations, such as T suppressor/cytotoxic cells and B cells, and the close association of the decrease in the number of T helper cells with AIDS are consistent with a distinct pathogenesis (and cause) for AIDS.

Immunological studies of homosexual men with immunodeficiency and Kaposi's sarcoma☆

Acquired immunodeficiency and Kaposis sarcoma are epidemic among homosexual men in the United States. We have identified three clinically distinct disease syndromes in homosexually active men: a syndrome of severe cellular immunodeficiency including infection with Pneumocystis carinii and other opportunistic pathogens, a syndrome of chronic benign lymphadenopathy without severe opportunistic infections, and Kaposis sarcoma. All 46 patients which we have studied with these three disease syndromes shared a common immune abnormality, that being a reduction in the circulating T-lymphocyte subpopulation bearing the Leu-3/OKT-4 antigen. The second major T-lymphocyte subpopulation, which bears the Leu-2/OKT-8 antigen, was numerically normal in all the disease syndromes, but increased as a percentage of all circulating lymphocytes. These abnormalities resulted in an inversion of the normal ratio of these two lymphocyte subpopulations. A similar, but less pronounced imbalance in circulating T-lymphocyte subpopulations was observed in a group of healthy homosexual men. The immune deficiency in these patients was most evident in the T-cell component of the immune system. Percentages of B cells, circulating immunoglobulin levels, and natural killer (NK) and antibody-dependent cell-mediated cytoxic (ADCC) functions were normal. Proliferative responses to antigen and mitogen were typically decreased in patients with the acquired immunodeficiency syndrome and some Kaposis sarcoma patients, but not those with the prolonged lymphadenopathy syndrome or a control group of healthy homosexual men. Possible causes or factors contributing to the immunodeficiency and interrelationships among the three disease manifestations are discussed.

Antibody to human T-lymphotropic virus type III in wives of hemophiliacs: evidence for heterosexual transmission.

To evaluate the risk of heterosexual transmission of the acquired immunodeficiency syndrome, lymphadenopathy, and infection with human T-lymphotropic virus type III (HTLV-III), we studied 42 hemophiliacs and their wives. By early 1984, 9 of the hemophiliacs had asymptomatic lymphadenopathy and 1 had the acquired immunodeficiency syndrome. Twenty-one hemophiliacs, including all 10 with clinically overt disease, had antibody to HTLV-III. None of the 42 wives had lymphadenopathy or the acquired immunodeficiency syndrome but 2 had HTLV-III antibody. One of these women had evidence of immunologic dysfunction with a markedly reduced T-helper/suppressor cell ratio. The husbands of these 2 women both had HTLV-III antibody, but neither had overt acquired immunodeficiency syndrome-related disease. Thus, as of early 1984, the prevalence of HTLV-III antibody in wives of hemophiliacs seropositive for HTLV-III was 9.5% (2 of 21). We conclude that transmission of HTLV-III occurs between hemophiliacs and their heterosexual partners.

Defective monocyte function in acquired immune deficiency syndrome (AIDS): evidence from a monocyte-dependent T-cell proliferative system.

T-cell proliferative responses to the mitogenic monoclonal antibody anti-Leu 4 were assessed in healthy controls, lymphadenopathy syndrome (LAS) patients, and acquired immune deficiency syndrome (AIDS) patients. While 19% of the control group showed low anti-Leu 4 responses (<12,000 cpm), 60% of the LAS patients, 71% of the AIDS-opportunistic infection patients, and 50% of the AIDS-Kaposis sarcoma patients showed low responses. T-cell responsiveness in healthy low responders was greatly enhanced by the addition of monocytes from an anti-Leu 4 high responder (responder monocytes). We therefore sought to determine if the low-responder state in LAS and AIDS patients was also mediated by monocytes and, thus, correctable by the addition of responder monocytes. In the LAS low-responder group, the level of enhancement by healthy responder monocytes was similar to that observed for the healthy low-responder group. In the AIDS low-responder group, however, the level of enhancement was significantly lower than that observed in the healthy low-responder and LAS low-responder groups. These findings suggest that impaired proliferation to anti-Leu 4 in LAS patients may be due to a monocyte defect similar to the monocyte defect responsible for low anti-Leu 4 responses in healthy controls. AIDS patients, however, show additional defects in anti-Leu 4-induced proliferation that are not fully corrected by the addition of responder monocytes.

The pediatric nephrologist's dilemma: growth after renal transplantation and its interaction with age as a possible immunologic variable.

Two important criteria for successful end-stage renal disease therapy in children are achievement of optimal growth and possession of a well-functioning renal transplant. We describe eight children with accelerated post-transplant growth. Accelerated and even catch-up growth was achievable if the transplant occurred at an early age (less than 9 years), the daily dose of prednisone was low (less than or equal to 0.24 mg/kg/d), and renal function was excellent (creatinine clearance greater than or equal to 89 mL/min/1.73 m2). However, the benefit to growth of transplanting a kidney in young children may be offset by reduced cadaver graft survival in children younger than 6 years. To study whether the less favorable graft survival was attributable to an increased immunologic responsiveness in the younger child, we examined three tests of nonspecific immune responsiveness, each of which, when increased, may indicate a propensity toward rejection: total T cell absolute number, T helper/suppressor ratio, and spontaneous blastogenesis. Each measurement was significantly increased in 20 uremic children 5 years old or younger, compared with 81 children 6 to 23 years of age. These data suggest that improved growth may be attained by transplanting a kidney in the young child with end-stage renal disease, but the young child may be at increased risk for rejection. This hypothesis suggests that for optimal rehabilitation, strategies should take into account the unique needs of the young child.

HLA studies in acquired immune deficiency syndrome patients with Kaposi's sarcoma

To investigate the possible contribution of genetic susceptibility to Kaposis sarcoma associated with acquired immune deficiency syndrome (AIDS-KS), 21 patients were typed for HLA-A, B, C, and DR antigens. Significantly increased frequencies of HLA-Aw23, and HLA-Bw49 antigens were observed in the Caucasian AIDS-KS group. In this same group, the frequencies of HLA-DR5 and HLA-Bw44 antigens were increased at the P less than 0.1 level. Increased frequencies of HLA-A29 and HLA-Cw4 antigens and a decreased frequency of HLA-B8 antigen were also noted, but with P greater than 0.1, in the Caucasian AIDS-KS group.

Azathioprine suppression of natural killer activity and antibody-dependent cellular cytotoxicity in renal transplant recipients.

The relative effects of azathioprine (AZA) and prednisone (PRED) on natural killer (NK) activity and the antibody-dependent cellular cytotoxicity (ADCC) of K (killer) cells and the number of FcR and other lymphoid cells were examined in renal transplant recipients. In addition to both long-term (>6 months) and short-term (<6 months) transplant recipients receiving conventional AZA-PRED therapy, an important group of long-term recipients receiving PRED but not AZA was studied for the first time. Both NK activity and ADCC are profoundly reduced in the long-term AZA-PRED group but are normal in the long-term PRED-alone (no-AZA) group. The short-term AZA-PRED group exhibits NK and ADCC levels significantly lower than normal but not as low as those of the long-term AZA-PRED group. Patient groups with low NK and ADCC also have low circulating Fc receptor-bearing (FcR) cells. A single patient in the long-term AZA-PRED group was removed from AZA therapy, and approximately 3 months was required for the patients suppressed NK and ADCC to return to normal. These findings indicate that AZA rather than PRED is the major drug important in suppressing ADCC and NK activity in renal transplant recipients. Several months are required for combination AZA-PRED therapy to reduce these cytotoxic activities. Similarly, several months are required for suppressed ADCC and NK activity to return to normal upon discontinuation of AZA.