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Biomedical subjects

R T Mitsuyasu

Publications and source records attributed to R T Mitsuyasu.

At least 19 recordsLinked to original sources
PubMed1992

Immune changes in HIV-1 infection: significant correlations and differences in serum markers and lymphoid phenotypic antigens.

Human immunodeficiency virus type 1(HIV-1) induces extensive immune cell alterations which can be detected by changes both in serum levels of soluble immune activation products and in several lymphoid phenotypic markers. The current studies were conducted in 70 HIV-1 seropositive subjects to determine whether changes among four important serum immune activation markers (neopterin, beta-2 microglobulin, soluble CD8, and soluble IL-2 receptor) and seven lymphoid phenotypic markers (CD38, HLA-DR, CD57, CD11b, CD45RA, leu8, and CD71) reflect similar or disparate aspects of immune pathology. On the basis of correlation coefficient calculation, four groups of related markers (Fig. 1) were identified: Group A, sIL-2R was related to group B where serum neopterin, beta 2M, sCD8 levels, and lymphocyte CD38 antigen expression correlated closely. Loss of CD45RA or Leu 8 antigens in group C correlated with group B and D markers increase. HLA-D in group D was a more distantly related immune activation marker. Phenotypic markers CD57, CD11b, and CD71 did not correlate with the immune activation processes reflected by the serum and phenotypic marker groups A-D. Correlations between serum and certain lymphoid phenotypic markers were generally stronger later in HIV-1 infection when CD4 levels were less than 500/mm3. This study provides information for selecting markers for investigating immune changes in HIV-1 infection and immune-related diseases. Many serum and lymphoid phenotypic markers reflect related aspects of immune dysregulation. However, some markers can indicate different aspects of disease.

ADP-ribosyl Cyclase↗
PubMed1992

The effect of zidovudine treatment on serum neopterin and beta 2-microglobulin levels in mildly symptomatic, HIV type 1 seropositive individuals.

Sixty-one subjects with mildly symptomatic human immunodeficiency virus (HIV) infection were included in a double-blind, randomized, placebo-controlled trial of zidovudine (part of AIDS Clinical Trials Group protocol 016, ACTG 016) to evaluate changes in the serum immune activation markers neopterin and beta 2-microglobulin (beta 2M) as early markers of the antiviral effect of zidovudine on HIV type 1 (HIV-1) infection. The mean values of serum neopterin and beta 2M levels in 27 placebo-treated subjects tended to increase with time. The mean value of neopterin in 34 subjects receiving zidovudine decreased at 4 weeks (15.76 nmol/L before treatment to 12.73 nmol/L, p = 0.001). The maximum reduction was seen at 8 weeks of treatment (10.78 nmol/L, p less than 0.0001). Subsequently, the mean value of serum neopterin increased but remained below the pretreatment value for more than a year. Serum beta 2M levels decreased (from 3.01 to 2.69 mg/L at 4 weeks, p = 0.01) and reached the lowest level at 8 weeks (2.45 mg/L, p = 0.0002) in zidovudine recipients. The mean beta 2M level returned to pretreatment value at approximately 24 weeks of the treatment. There was a close correlation between changes from baseline in serum neopterin and beta 2M during the first 16 weeks of the zidovudine therapy, but not later. Subjects with greater reductions of serum neopterin or beta 2M tended to maintain lower levels of these markers with continued zidovudine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Complex↗
PubMed1992

Eleven lymphoid phenotypic markers in HIV infection: selective changes induced by zidovudine treatment.

HIV infection induces substantial changes in the expression of many lymphocyte phenotypic markers as well as depletion of CD4 lymphocyte numbers. A comprehensive study was undertaken to determine whether seven lymphocyte phenotypic changes associated with HIV infection (increased CD38, HLA-DR, CD57, and CD71 and decreased CD11b, CD45RA, and leu-8) are altered by zidovudine (ZDV) administration. Levels of the four major lymphoid subsets (CD4, CD8, B, and NK cells) and changes in the serum activation markers neopterin and beta 2-microglobulin (beta 2M) were also measured. Elevated pretreatment expression of CD38 and CD71 was reduced significantly toward normal at 2 weeks by ZDV; however, CD38 and CD71 returned to pretreatment levels at different rates. The kinetics of CD38 reduction and the return to pretreatment levels were similar to those of serum neopterin and beta 2M. HLA-DR decreased in many but not all subjects. CD4 lymphocytes showed a transient increase, most evident at 8 weeks of treatment. Lymphoid phenotypes that did not show significant changes after ZDV therapy included CD57, CD11b, CD45RA, and leu-8 markers as well as CD8 T cells, CD20 B cells, and CD56 NK cells. The fact that some lymphocyte phenotypic markers change toward normal with ZDV treatment and others do not indicates that complex processes underlie immune perturbations of HIV infection. Several phenotypic markers (CD38, CD71, and HLA-DR) that are susceptible to short-term effects of ZDV (but with changes that differ from CD4 T cell changes) are surrogate marker candidates for evaluation in anti-HIV treatment.

Biomarkers↗
PubMed1991

Potential use of human stem cell factor as adjunctive therapy for human immunodeficiency virus-related cytopenias.

Hematopoietic dysfunction with peripheral cytopenias is a common complication of human immunodeficiency virus (HIV) infection. Symptomatic anemia is the most common cytopenia and occurs in the presence and absence of myelosuppressive drug therapy such as zidovudine. Drug-induced neutropenia and immune thrombocytopenia are also frequent and occur in up to 50% of acquired immunodeficiency syndrome (AIDS) patients. Attempts to reduce the impact of bone marrow failure have focused on dose reduction of zidovudine, ganciclovir, and chemotherapy, and the use of recombinant hematopoietic hormones such as erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF). Despite these maneuvers, approximately 30% of patients with AIDS receiving zidovudine will become transfusion-dependent. This has led to investigations of other cytokines that may increase blood cell formation. The recent identification of decreased number and proliferation of hematopoietic progenitors in patients with HIV infection suggests that agents which have activity on progenitor cell pools may have clinical utility. We demonstrate that human stem cell factor (HuSCF) increases burst-forming unit-erythroid (BFU-E), colony-forming unit-granulocyte-monocyte (CFU-GM), and CFU-Mix formation in vitro in normal and HIV-infected individuals. HuSCF also decreases the sensitivity of BFU-E to inhibition by zidovudine without altering HIV replication in lymphocytes or monocytes, altering peripheral blood mononuclear cell proliferation to phytohemagglutinin (PHA) and interleukin-2 (IL-2) or altering the effectiveness of zidovudine or dideoxyinosine in inhibiting HIV replication in lymphocytes or monocytes. These studies suggest that HuSCF may have clinical utility in HIV infection as an adjunctive treatment for HIV-related cytopenias.

AIDS-Related Complex↗
PubMed1991

Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine.

Twenty-two patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex and multilineage hematopoietic defects were treated with recombinant granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) in a phase I/II trial. All patients were neutropenic and anemic after withdrawal of all bone marrow-suppressive drugs. Daily, G-CSF was subcutaneously self-administered until an absolute neutrophil count (ANC) greater than 6,000/microL was achieved and maintained for 2 weeks. Subcutaneous EPO was added to the regimen and the dose increased until an increase of 15 g/L of hemoglobin was observed. Groups of patients were administered increasing doses of zidovudine to determine their tolerance. G-CSF and EPO therapy was continued with dose modification to maintain an ANC greater than 1,500/microL and hemoglobin greater than 100 g/L. The dose of zidovudine was not altered. All 22 patients responded to G-CSF with a mean 10-fold increase in neutrophils occurring in less than 2 weeks. Significant increases in CD4 and CD8 cell number, lymphocyte proliferative response, and bone marrow cellularity were seen. EPO therapy increased hemoglobin in all 20 evaluable patients within 8 weeks. Sixteen patients received 1,000 mg and four patients received 1,500 mg of zidovudine per day. The reinstitution of zidovudine resulted in a decline in reticulocytes and hemoglobin and the reappearance of transfusion requirements in eight of the 20 patients, six of whom had the study medications stopped. No patient had the study medications stopped because of neutropenia or thrombocytopenia. Toxicities were mild and did not require dose modifications. Limiting dilution plasma and lymphocyte co-cultures for HIV as well as serum p24 antigen levels did not change significantly during G-CSF or combined G-CSF and EPO therapy. HIV p24 antigen decreased significantly with zidovudine therapy. Opportunistic infections occurred in 14 patients but were successfully treated with myelosuppressive antimicrobial agents, including ganciclovir, without the development of neutropenia. These results suggest that combined therapy with G-CSF and EPO may improve the neutropenia and anemia of AIDS. Combined therapy may allow the resumption of full-dose zidovudine in most patients intolerant of the hematologic effects of zidovudine without apparent alteration of HIV expression or the efficacy of zidovudine.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Human T-cell leukemia virus infection in non-intravenous drug using HIV seropositive men in Los Angeles.

Sera from 634 homosexual men with Western blot-confirmed human immunodeficiency virus (HIV) infection were subjected to radioimmunoprecipation assay (RIPA) using an HTLV-I-infected human T-cell line (SLB-I). Sera obtained from Japanese adult T-cell leukemia patients, noninfected healthy individuals served as positive and negative controls. HIV-infected groups were comprised of asymptomatic homosexuals (n = 131), AIDS-related complex (n = 115), Kaposi's sarcoma (n = 300), AIDS-defining opportunistic infections (n = 76), and high-grade lymphomas (n = 12). Only two patients were known to be intravenous drug users. No instances of dual retroviral infection were detected. As a corollary, no cross reactivity between HTLV and HIV gene products was noted by RIPA. We conclude that HTLV infection is uncommon among select groups of HIV seropositive homosexuals who do not engage in intravenous drug abuse. Additional studies examining the seroprevalence and consequence of HTLV infection in broader based populations at risk for retroviral infection are required.

Adult↗
PubMed1991

Interferon-alpha 2a in the treatment of acquired immunodeficiency syndrome-related Kaposi's sarcoma.

In a series of studies, recombinant interferon-alpha 2a (rIFN alpha 2a, Roferon-A) was administered alone (273 men) or combined with vinblastine (91 men) to patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Patients were treated with daily doses of rIFN alpha 2a ranging from 3 to 54 million international units (I.U.) administered intramuscularly. A dose of 36 million I.U. daily for approximately 10 weeks followed by a three times weekly maintenance schedule with the same dose resulted in the best overall therapeutic benefit. An escalating-dose regimen of 3, 9, and 18 million I.U. daily, each for 3 days, followed by 36 million I.U. daily, produced equivalent therapeutic benefit with amelioration of acute toxicity in some patients. Response was more likely in patients without a history of opportunistic infection or B symptoms (fever, night sweats, or weight loss). Response rate increased with increasing baseline CD4 lymphocyte count and was 45.5% in patients with a CD4 count of greater than 400/mm3. Responding patients with a CD4 count of greater than 200/mm3 had a distinct survival advantage over patients who had similar CD4 counts but whose tumors did not regress with therapy. The addition of vinblastine increased toxicity and did not improve the response rate or prolong survival. Side effects included fatigue, fever, chills, myalgias, headaches, anorexia, nausea, diarrhea, and dizziness. Mild abnormalities in hematologic and liver function tests occurred in some patients. Most adverse effects diminished or resolved with continued therapy. We conclude that rIFN alpha 2a offers important therapeutic benefit in a select group of patients with AIDS-related KS.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Interferon alpha in the treatment of AIDS-related Kaposi's sarcoma.

Interferon alpha was one of the first drugs tested for the treatment of patients with AIDS-related Kaposi's sarcoma based on its known antiviral properties and its abilities to modulate immune function and inhibit neoplastic cell proliferation. In vitro studies demonstrated defective production of interferon by blood cells of HIV-infected individuals and suppression of HIV replication by interferons alpha and beta. Interferons have also been shown to inhibit angiogenesis induced by tumour cells or by allogeneic lymphocytes in mice. The efficacy of recombinant interferon alpha for the treatment of AIDS-related Kaposi's sarcoma has been well documented with antitumour responses seen in approximately 30% of all patients treated in single agent efficacy trials with doses of at least 20 MU/m2. In several uncontrolled studies, response of Kaposi's sarcoma to treatment with interferon alpha was associated with longer survival and few opportunistic infections. Tumour response appears to be correlated with an absence of opportunistic infection and with CD4 cell numbers. Several studies using high interferon alpha doses have demonstrated decreases in serum HIV P24 core antigens which appear to be confined to patients whose tumours also regressed. The use of interferon alpha in HIV-infected patients with or without Kaposi's sarcoma have demonstrated in vivo anti-HIV activity. Studies have recently evaluated the tolerance and therapeutic potential of interferon alpha in combination with the reverse transcriptase inhibitor, zidovudine (azidothymidine AZT). Synergistic suppression of HIV replication in vitro has been demonstrated with the combination of interferon alpha and zidovudine. The description of HIV isolates with reduced sensitivity to zidovudine following prolonged treatment, and the finding that interferon alpha, but not zidovudine, prevents HIV expression in chronically infected cell lines, suggests that this combination might be useful in long-term treatment of patients with HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Hematologic abnormalities in AIDS.

The hematologic manifestations of HIV infection include morphologic abnormalities of peripheral blood and bone marrow changes. Laboratory abnormalities, including measures of coagulation, serum vitamin B12 levels, and positive Coombs's test, are seen with HIV infection and may not carry the same clinical consequence as when noted in non-HIV infected populations. Antibodies to circulating red blood cells, platelets, and granulocytes may represent alterations in autoimmunity or nonspecific HIV-induced B-cell stimulation, but they do not necessarily correlate with development of peripheral blood cytopenias. The advent of commercially available hematopoietic growth factors has allowed greater insight into specific host-virus-drug interactions that may be important in regulating viral growth and expression. Novel clinical approaches using hematopoietins alone or in combination with antimicrobial, antiviral, and antitumor drugs represent exciting developments in the treatment of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1991

The use of hematopoietic hormones in HIV infection and AIDS-related malignancies.

Three hematopoietic stimulants have been used in patients with HIV infection and a variety of AIDS-related complications. Both G-CSF and GM-CSF have demonstrated the ability to correct leukopenia related to HIV infection and ameliorate the drug-related myelosuppressive effects of zidovudine, trimethoprim/sulfamethoxazole, ganciclovir, and, in the case of GM-CSF, alpha-interferon, and cancer chemotherapies. Erythropoietin has been successfully used to ameliorate the anemia associated with HIV infection and zidovudine therapy. Treatment with these hematopoietic stimulants is very well tolerated with minimal toxicity. Of the granulocyte stimulants, G-CSF appears to induce fewer side effects than GM-CSF in trials conducted to date. Future trials demonstrating that the amelioration of hematopoietic suppression by the colony-stimulating factors results in increased clinical response rates and improved survival are necessary to fully assess the value of this approach in the care of HIV-infected patients.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Recombinant human granulocyte colony-stimulating factor increases circulating burst forming unit-erythron and red blood cell production in patients with severe human immunodeficiency virus infection.

Erythropoietin (EPO) is a major regulatory factor controlling red blood cell (RBC) production in humans. Although other humoral factors can alter the proliferation of committed early erythroid progenitors in vitro, no factor other than EPO has been clearly shown to induce proliferation of these cells in vivo. In a clinical trail of recombinant granulocyte colony-stimulating factor (G-CSF) and recombinant EPO in patients with advanced human immunodeficiency virus (HIV) infection, we noted reticulocytosis and increases in hemoglobin when G-CSF was administered before the administration of EPO. Subsequent studies demonstrated a significant increase in circulating burst forming unit-erythron (BFU-E) during daily recombinant G-CSF therapy. This increase was both time- and dose-dependent. The magnitude of increase in BFU-E correlated with the magnitude of increase in neutrophils and was associated with a mean increase in reticulocytes of 32,363/microL and a significant increase in mean hemoglobin of 1.04 +/- 0.34 g/dL over an 18-day interval. There was a significant increase in iron binding capacity and decreases in iron saturation and ferritin levels. In patients who were not recently transfused, there was an associated fall in endogenous erythropoietin levels. The increase in RBC production was most marked in patients who were severely anemic, transfusion-dependent, and who had elevated pretreatment EPO levels. There was no correlation between the increase in BFU-E and endogenous EPO levels or the time since last dose of zidovudine. The addition of recombinant EPO therapy three times weekly to patients did not result in further significant increases in BFU-E but did significantly increase hemoglobin. Our data suggest that recombinant G-CSF may be one of the hematopoietic factors that influences production of BFU-E and RBCs in humans.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Beta-interferon therapy in patients with poor-prognosis Kaposi sarcoma related to the acquired immunodeficiency syndrome (AIDS). A phase II trial with preliminary evidence of antiviral activity and low incidence of opportunistic infections.

STUDY OBJECTIVE: To study the efficacy of high doses of beta-ser-interferon (recombinant human 17-serine beta-interferon) in patients with human immunodeficiency virus (HIV) infection and Kaposi sarcoma. DESIGN: A nonrandomized, controlled trial of two high-dose regimens of beta-ser-interferon administered until tumor progression, toxicity, or an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection occurred. SETTING: An AIDS treatment clinic at a tertiary care center. PATIENTS: A sequential sample of 39 patients with biopsy-proven, AIDS-related Kaposi sarcoma were enrolled during a 2-year period. Thirty-eight patients were evaluable for response. Most patients (35 of 38) had one or more of the following clinical or laboratory predictors for a poor response to interferon therapy: HIV p24 antigenemia, low CD4 cell numbers, elevated beta 2-microglobulin levels, previous opportunistic infections, or previous systemic chemotherapy. INTERVENTIONS: Beta-ser-interferon was self-administered subcutaneously at home 5 days per week. The first 21 patients used 90 million IU/d, and the remainder used 180 million IU/d. MEASUREMENTS AND MAIN RESULTS: Six patients (16%) had a major clinical response, and 15 (39%) had stable disease for prolonged periods. Toxicities were minimal; the major toxicity was a skin reaction at the injection site. The HIV p24 antigen level declined more than 50% in 8 of the 19 patients with initial values greater than 50 pg/mL. Antiretroviral activity and antitumor activity were seen only in patients with normal initial beta 2-microglobulin levels. Minimal changes were seen in CD4 and CD8 cell numbers. Only 1 patient had an opportunistic infection while on study, but five other patients developed infections after treatment was discontinued for an incidence of six opportunistic infections in 285 patient-observation months. CONCLUSIONS: The high doses of interferon did not improve the major response rate in patients with poor-prognosis, AIDS-related Kaposi sarcoma. There was, however, a suggestion of antiviral activity in patients with normal beta 2-microglobulin levels and a decrease in the expected incidence of opportunistic infections.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Infection with HIV is associated with elevated IL-6 levels and production.

Polyclonal B cell activation is commonly observed in AIDS and in infection with HIV. Because IL-6 (B cell stimulatory factor 2) plays an essential role in the differentiation of activated B cells to Ig-secreting cells, and because IL-6 production is induced by exposure of human PBMC to HIV, we measured the level of circulating plasma IL-6, spontaneously-produced IL-6, and IL-6 mRNA in HIV-infected donors and in healthy control donors. Elevated levels of plasma IL-6 and IL-6 mRNA were detected in HIV-infected donors. PBMC isolated from the peripheral circulation of HIV-infected donors, and cultured without added exogenous activators of IL-6 production, produced markedly elevated amounts of IL-6 when compared with cells isolated from healthy donors. Interestingly, levels of an acute-phase protein, which is known to be induced by IL-6, was also increased in HIV-infected donors. These results demonstrate that elevated levels of IL-6 are associated with HIV-infection, and suggest that IL-6 over-production may contribute to the polyclonal B cell activation seen in AIDS and HIV infection.

C-Reactive Protein↗
PubMed1990

The use of myeloid hematopoietic growth factors in patients with HIV infection.

Hematologic abnormalities are frequent occurrences in patients with HIV infection. Myelosuppression in AIDS may be due to multiple factors and has significant impact on the treatment of HIV-infected individuals, as it is the major dose-limiting toxicity of a number of antimicrobial compounds and chemotherapy. Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are hematopoietic hormones which effect myeloid progenitor cells and enhance the function of mature neutrophils. Clinical studies of the effects of these agents in patients with AIDS indicate that GM-CSF and G-CSF can increase the production of leukocytes in a dose-dependent fashion. This increase in leukocyte production may allow the continued administration of full doses of antiviral or other myelosuppressive medications in previously hematologically intolerant patients with AIDS. Investigations of the hematopoietic, virologic, and immunologic effects of these agents alone and in combination with other hematopoietins, cytokines, and chemotherapeutic agents will ultimately define their clinical utility in patients with HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1990

AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6.

Cell lines derived from Kaposi sarcoma lesions of patients with AIDS (AIDS-KS cells) produce several cytokines, including an endothelial cell growth factor, interleukin 1 beta, and basic fibroblast growth factor. Since exposure to human immunodeficiency virus increases interleukin 6 (IL-6) production in monocytes and endothelial cells produce IL-6, we examined IL-6 expression and response in AIDS-KS cell lines and IL-6 expression in AIDS Kaposi sarcoma tissue. The AIDS-KS cell lines (N521J and EKS3) secreted large amounts of immunoreactive and biologically active IL-6. We found both IL-6 and IL-6 receptor (IL-6-R) RNA by slot blot hybridization analysis of AIDS-KS cells. The IL-6-R was functional, as [3H]thymidine incorporation by AIDS-KS cells increased significantly after exposure to human recombinant IL-6 (hrIL-6) at greater than 10 units/ml. When AIDS-KS cells (EKS3) were exposed to IL-6 antisense oligonucleotide, cellular proliferation decreased by nearly two-thirds, with a corresponding decrease in the production of IL-6. The decrease from IL-6 antisense in AIDS-KS cell proliferation was reversed by the addition of hrIL-6. We confirmed that AIDS-KS cells produced IL-6 in vivo by preparing RNA and tissue sections from involved and uninvolved skin from a patient with AIDS Kaposi sarcoma. We detected immunoreactive IL-6 in the involved tumor areas and to a lesser extent in the surrounding normal epidermis. Slot blot hybridization showed a great excess of IL-6 and IL-6-R RNA in involved skin compared to uninvolved skin. These results show that both IL-6 and IL-6-R are produced by AIDS-KS cells and that IL-6 is required for optimal AIDS-KS cell proliferation, and they suggest that IL-6 is an autocrine growth factor for AIDS-KS cells.

Acquired Immunodeficiency Syndrome↗