Biomedical subjects
Publications and source records attributed to H Masur.
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To examine the defect in cellular immunity in patients with acquired immunodeficiency syndrome (AIDS), we studied in vitro lymphocyte proliferation and interferon (IFN) release in response to cytomegalovirus (CMV) antigen and Concanavalin A mitogen in 40 homosexual men with AIDS, 10 homosexual men with chronic lymphadenopathy syndrome, 7 healthy homosexual men, and 18 healthy heterosexual subjects of either sex. CMV serology by an enzyme-linked immunosorbent assay and viral cultures for CMV were performed. Lymphocytes of patients with AIDS showed impaired CMV-specific release of IFN but normal mitogen-induced IFN release. The defect was not attributable to CMV infection per se. Cell proliferation in response to both CMV antigen and mitogen was impaired in patients with AIDS who had opportunistic infections. The defect could not be attributed to CMV viremia. We concluded that impaired release of IFN in response to a viral antigen is characteristic of lymphocytes in patients with AIDS and that this defect is distinct from a defect in mitogenic responsiveness, which coexists predominantly in patients with opportunistic infections.
Patients with acquired immune deficiency syndrome may develop infection with mycobacteria, particularly Mycobacterium avium-M. intracellulare (MAI). These infections can frequently be associated with demonstrable mycobacteremia with the organism. In this study, we compared the sensitivity of a radiometric (BACTEC system; Johnston Laboratories, Inc., Towson, Md.) liquid medium culture system with that of conventional solid mycobacterial culture media for cultures of blood from these patients. Both systems were inoculated with blood concentrate prepared by lysis-centrifugation (Isolator; Du Pont Co., Wilmington, Del.). Of 46 acquired immune deficiency syndrome patients whose blood was cultured, 28% had cultures positive for MAI. Patients had from less than 1 to more than 100 MAI colonies per ml of blood. Lowenstein-Jensen and Middlebrook 7H11 agars were comparable in recovery of MAI. BACTEC 12A vials containing double the standard volume of medium (4 ml) were more sensitive and were positive slightly earlier than vials containing the standard volume (2 ml). Conventional media detected 98% of positive cultures; BACTEC vials containing double volumes of medium detected 94% of positive cultures, whereas single-volume vials detected 77%. BACTEC vials were positive approximately 5 to 6 days sooner than slants or plates containing conventional media. For a few cultures, the use of unconcentrated blood was compared with the use of Isolator-concentrated blood by using each of these as inocula for BACTEC vials. Results for these cultures suggested that, although the use of Isolator-concentrated blood resulted in greater sensitivity than the use of unconcentrated blood would, the use of unconcentrated blood would still result in the detection of at least 78% of positive cultures.
We studied the effects of sera from patients with the acquired immunodeficiency syndrome (AIDS) on interleukin-2 (IL-2) production to help elucidate the mechanism of immunodeficiency. Compared with sera from healthy controls, sera from AIDS patients suppressed phytohemagglutinin (PHA)-induced IL-2 production by normal blood mononuclear cells. Sera from homosexual contacts of AIDS patients and from adults with acute cytomegalovirus infection generally lacked this suppressive activity. The effect of the AIDS sera could not be attributed to absence of a stimulatory or nutritive factor, to inactivation of IL-2, to inhibition of the IL-2 assay, nor to increased turnover of IL-2. The suppressive effect of the sera was not mediated by radiosensitive or T8 antigen-bearing suppressor cells or by increased prostaglandin production or decreased interleukin-1 production. The sera acted directly on the groups of cells that produce IL-2, T cells and large granular lymphocytes; suppression occurred at an early, probably pretranslational, stage. When cells were incubated with AIDS sera and then washed, the suppressive effect persisted. The sera did not cause direct or complement-mediated cytotoxic effects on normal mononuclear cells nor did they suppress PHA-induced interferon production, nor proliferation of T lymphoblasts or lymphocyte lines. The suppressive effect was not mediated by interferon, cortisol, immunoglobulin G or M, or immune complexes. The activity was stable at pH 3, pH 10, and 60 degrees C; inactivated at 100 degrees C; and not ether extractable. Because IL-2 plays a central role in the development of many immune responses, the serum factor(s) that inhibits IL-2 production could contribute significantly to the immunodeficiency of AIDS.
AIDS associated retrovirus-like particles were identified in the salivary gland, prostate and/or testicle of two AIDS patients. These findings further suggest that saliva and semen may transmit the infection to susceptible individuals.
Although an aggressive form of Kaposi's sarcoma often develops in patients with the acquired immunodeficiency syndrome, most patients die due to opportunistic infections rather than the direct effects of this tumor. Because Kaposi's sarcoma has caused pulmonary dysfunction in a number of our patients, we attempted to characterize features of pulmonary dysfunction induced by Kaposi's sarcoma. In 66 patients with Kaposi's sarcoma treated between 1982 and 1984 there were 30 episodes of pulmonary dysfunction that resulted in a biopsy. Six episodes were due to pulmonary Kaposi's sarcoma alone, and 6 additional episodes were due to Kaposi's sarcoma and associated opportunistic infections. Clinical and radiologic features of pulmonary Kaposi's sarcoma an infection were indistinguishable. Pulmonary Kaposi's sarcoma could only be documented in large tissue sections available from open-lung biopsy or autopsy samples. Because chemotherapy or radiation therapy appears to provide palliation, clinicians should recognize Kaposi's sarcoma as a cause of pulmonary disease in patients with the acquired immunodeficiency syndrome.
The acquired immunodeficiency syndrome continues to be a major public health problem in the United States, and recently its spread worldwide has accelerated. The syndrome is caused by a human retrovirus transmitted by sexual contact and via blood or blood products. The virus has been isolated, characterized, and cloned, and in addition to its presence in blood, it has been found in body tissues and fluids including brain, semen, and saliva. Although the syndrome in the United States is still largely confined to male homosexuals and intravenous drug users, there is increasing evidence, particularly from Zaire, that the virus can be spread by heterosexual contact. Attempts at immune reconstitution with lymphocytes and lymphokines have resulted in some transient improvement in immune function but without clinical effect, indicating the need for specific anti-retroviral therapy in combination with immune reconstitution.
The Acquired Immunodeficiency Syndrome (AIDS) is a recently recognized syndrome caused by a newly described retrovirus, Human T-Cell Lymphotropic Virus-III(HTLV-III). A disease that selectively attacks the immune system, manifested by opportunistic infections and unusual neoplasms, AIDS has continued to be confined primarily to several unique at-risk populations. AIDS has evoked unprecedented interest in the medical community, and care of patients with this nearly universally fatal syndrome presents many unique challenges to the health care team.
The immune systems of patients with acquired immunodeficiency syndrome are characterized by a profound defect in the number and function of helper/inducer T-lymphocytes, particularly at the level of soluble antigen recognition. Due to this selective yet profound defect in the immune system, these patients are prone to recurrent severe opportunistic infections and Kaposi's sarcoma. While therapies exist for some of these complications of acquired immunodeficiency syndrome, no effective therapies exist for the underlying immune defect of this syndrome. Reviewed here are some of our recent attempts at immune reconstitution in acquired immunodeficiency syndrome, using either whole scale immune reconstitution through the use of lymphocyte transfers and bone marrow transplantation or enhancement of the remaining immune systems with the T-cell-derived lymphokines interleukin-2 or immune gamma-interferon. In addition, recent advances in the therapy of Pneumocystis carinii pneumonia and disseminated cytomegalovirus disease are discussed.
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Patients with the acquired immunodeficiency syndrome (AIDS) exhibit a variety of disorders of cellular immunity, including a deficient ability to generate cytotoxic T cells and depressed levels of natural killer (NK) cell activity. Interleukin 2 (IL 2) in vitro can markedly augment these depressed immune functions. Because IL 2 can induce the release of interferon-gamma (IFN-gamma) from normal peripheral blood lymphocytes (PBL), and because IFN-gamma may play a role in the regulation of NK cell activity, this study was performed to determine if the IL 2 enhancement of the NK cell activity of patients with AIDS was an IFN-gamma-dependent effect. PBL from eight healthy heterosexual donors and from nine patients with AIDS were studied for their ability to release IFN-gamma in response to IL 2 at a concentration of 100 U/ml. After 60 hr of culture, the PBL of all eight healthy donors produced IFN-gamma with a mean titer of 113 U/ml (range 40 to 320 U/ml). In contrast, the PBL from only two of nine patients with AIDS released measurable amounts of IFN-gamma (40 U/ml each) in response to IL 2 with a mean titer of 13.5 U/ml for all nine. Although the PBL from patients with AIDS were deficient in their capacity to produce IFN-gamma in response to 100 U/ml of IL 2, significant enhancement of NK cell activity could be obtained after only 1 hr of PBL treatment with 10 U/ml of IL 2, with an optimal NK enhancing effect occurring at doses of 50 to 100 U/ml of IL 2. The use of an anti-IFN-gamma monoclonal antibody resulted in complete neutralization of the IFN released from the normal PBL cultured with IL 2, but failed to inhibit the IL 2 enhancement of NK cell activity. Exogenous IFN-gamma exhibited different kinetics of enhancement of NK cell activity when compared to IL 2, requiring substantially more than 1 hr of pretreatment of PBL. These results indicate that the PBL from patients with AIDS usually do not release IFN-gamma when cultured with IL 2, and that IL 2 enhancement of the depressed NK cell activity of these patients may be an IFN-gamma-independent event. These results may have important implications for the therapy of AIDS.
Two of three chimpanzees given plasma from patients with acquired immune deficiency syndrome (AIDS) or pre-AIDS showed serum antibodies to type III human T-cell leukemia virus (HTLV-III) 10 to 12 weeks after transfusion. One animal also developed lymphadenopathy, transient depression of the ratio of T4 to T8 lymphocytes, and impaired blastogenic responses. No opportunistic infections occurred. Adenopathy persisted for 32 weeks, and antibody to HTLV-III persisted for at least 48 weeks. This transmission of HTLV-III by lymphocyte-poor plasma confirms the potential risk of such plasma or plasma derivatives to recipients. The susceptibility of the chimpanzee to HTLV-III infection and the ability to simulate the human lymphadenopathy syndrome in this animal makes it a valuable model for further study of AIDS.
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Herpesvirus infections were studied in persons with or at risk for the acquired immune deficiency syndrome (AIDS). The infections diagnosed were as follows: patients with AIDS, cytomegalovirus (CMV) in 34 of 34, Epstein-Barr virus (EBV) in 33 of 34, herpes simplex viruses (HSV) in eight of 34, and varicella zoster virus in four of 34; patients with chronic lymphadenopathy syndrome, CMV in eight of nine and EBV in nine of nine; in healthy homosexual men, CMV in five of 13 and EBV in seven of eight. Cytomegalovirus infections were frequently related to disease and death. Herpesvirus infections are frequent causes of serious diseases in AIDS. The prevalence of EBV and CMV infections in AIDS and the chronic lymphadenopathy syndrome may be the result of an important interaction between these viruses and the cause of AIDS.
To examine the cellular immune defect that predisposes patients with the acquired immunodeficiency syndrome (AIDS) to opportunistic infections, we tested T lymphocytes from 16 patients for the capacity to secrete macrophage-activating products (lymphokines) including gamma interferon. Mononuclear cells from 10 of 11 patients did not generate an effective lymphokine in response to mitogen, and 11 of 16 produced subnormal levels of gamma interferon (less than 300 U per milliliter). In addition, upon stimulation with specific microbial antigen, cells from none of 14 patients generated active lymphokines, and cells from 13 to 14 completely failed to secrete gamma interferon. However, the antimicrobial function of monocytes from the patients was intact, and once stimulated with normal lymphokines or gamma interferon alone, macrophages derived from patients' monocytes responded with enhanced and effective intracellular antimicrobial activity. These results suggest that impaired lymphokine production may predispose patients with AIDS to opportunistic infections, and they provide a rationale for using gamma interferon as immunotherapy.
Antilymphocyte antibodies were studied using the Terasaki microcytotoxicity technique in 21 gay patients including 7 with Kaposi's sarcoma, 5 with opportunistic infection, and 9 with lymphadenopathy syndrome. A significant increase in lymphocyte-reactive antibody was noted in 61% of this group. Similar studies using serum from 25 apparently healthy gay males showed lymphocytotoxic antibody in only one instance. When isolated T-cell subsets (OKT4+ or OKT8+) were utilized, a few sera from acquired immune deficiency syndrome (AIDS) patients apparently showed preferential killing for helper-inducer or suppressor-cytotoxic T-cell subsets, however, this showed no correlation with T-cell phenotypic profiles of OKT4 or OKT8+ cells in concurrent peripheral blood studies. When isolated normal OKT4 or OKT8 T-cell subsets were treated with complement and AIDS serum showing apparent T-cell subset specificity and treated T cells added to B cells, macrophages, and OKT4 or OKT8 cells cultured with pokeweed mitogen, no discernible effect on either help or suppression of IgG or IgM synthesis was recorded.
Forty patients with acquired immunodeficiency syndrome (AIDS) were examined for ocular abnormalities. Twenty of these patients died and the eyes were obtained for culture and histopathologic examination. These patients have multiple opportunistic infections and neoplasms as the result of a severe depression of cellular immunity. Fifty percent of all patients with AIDS and 75% of the autopsy group have ocular signs attributable to AIDS. Ocular findings were confined to four major categories: cytomegalovirus retinitis (10 patients), retinal cotton wool spots (11 patients), conjunctival Kaposi's sarcoma (2 patients) and neuro-ophthalmic motility abnormalities (3 patients). Cytomegalovirus retinitis was a significant cause of visual loss. Seven of 40 autopsy eyes had hand motion or worse visual acuity prior to the patients' death because of CMV retinitis. This necrotic retinitis showed minimal inflammation and progressed to involve the entire retina in three to six months, resulting in a gliotic retinal membrane. Therapy with antiviral agents was not effective. Recognizing the ocular signs of AIDS may facilitate the diagnosis. The ophthalmologist also has a major role in the observation of progression or regression of these ocular manifestations, and can assist in the evaluation of therapy in patients with AIDS.
Blood samples from a series of 12 patients with Kaposi's sarcoma or infectious complications of the acquired immunodeficiency syndrome (AIDS) and from 18 homosexual contacts of AIDS patients were screened for interferon-related tubuloreticular inclusions (TRI) in circulating leukocytes. In the AIDS patients, TRI were detected by transmission electron microscopy in 1.5 to 10% of mononuclear cell sections. They were most frequent in patients with a decreased fraction of T helper cells and T4/T8 ratios less than 0.2. Only rare TRI-positive sections were found in 3/12 homosexual contacts with lymphadenopathy and 1/6 asymptomatic contacts. Serum interferon was found to be elevated in each AIDS case tested, but was not a sufficient condition for detection of TRI in homosexual contacts. Active DNA virus infections, including cytomegalovirus, were common to the AIDS cases and possibly contributed to the TRI pathogenesis. Localization of TRI in T suppressor/cytotoxic cells was demonstrated with monoclonal anti-Leu 2a antibodies. The pathophysiologic significance of interferon stimulation with formation of TRI in immunocompetent cells requires further investigation.