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Biomedical subjects

T C Merigan

Publications and source records attributed to T C Merigan.

At least 163 records · Page 9Linked to original sources
PubMed1987

Native and recombinant herpes simplex virus type 1 envelope proteins induce human immune T-lymphocyte responses.

The abilities of whole herpes simplex virus type 1 (HSV-1) antigen (HSV-ag) and purified HSV-1 native and recombinant envelope proteins to stimulate in vitro T-lymphocyte responses were compared in patients with recurrent herpes labialis. Immunochemically purified preparations of native glycoproteins B, C, and D (ngB, ngC, ngD) from cultured HSV-1 as well as expressed recombinant plasmid preparations of gD (rgD-1t, rgD-45K) elicited lymphocyte proliferation (LT) and production of gamma interferon (IFN-gamma) and interleukin-2 (IL-2) only in seropositive individuals. The IFN-gamma induced by rgD-1t correlated with the time to the next herpetic lesion in 19 volunteers followed to recurrence (r = 0.69, P less than 0.008), although the magnitude and frequency of LT and IFN-gamma responses were lower with either recombinant or native purified antigens than with the whole-virus antigen. Combinations of ngB plus ngD or ngB plus ngC plus ngD stimulated more IFN-gamma, equivalent to whole-virus-antigen responses. Recombinant-derived human IL-2 also specifically increased LT and IFN-gamma responses in antigen-driven cultures. ngD stimulated IL-2 and LT responses similar to those of whole-virus antigen and higher than those of ngC. HSV-ag and ngB induced significantly higher titers of total IFN than could be accounted for by IFN-gamma; this was not seen for the other antigens, which induced only IFN-gamma. HSV-ag-driven Leu 2a-, plastic-nonadherent blood cells, unlike whole peripheral blood mononuclear cells, showed evidence of an increase and then a decline in the frequency of HSV-responsive cells after a lesion recurrence. These studies suggest that HSV-1 envelope proteins are capable of stimulating an immune T-helper-cell response which is associated with the prevention of human herpes simplex lesion recurrence. Although the whole virus probably contains additional important antigens, increasing concentrations or combinations of certain purified glycoproteins or the addition of nonspecific enhancers of T-lymphocyte function can drive in vitro immune responses to the same level as the complete set of viral antigens.

Antigens, Viral↗
PubMed1987

Regulation by recombinant interleukin-2 of protective immunity against recurrent herpes simplex virus type 2 genital infection in guinea pigs.

The goal of our study was to determine whether recombinant interleukin-2 (rIL-2) could modify the recurrence pattern of chronic herpes simplex virus type 2 (HSV-2) genital infection in guinea pigs. Animals that developed symptomatic acute HSV-2 infection were distributed at 14 days after viral inoculation into several treatment groups, which were similar with respect to the severity of acute disease. Three rIL-2 dosages administered for 4 weeks in daily subcutaneous injections were tested in this study: 5 X 10(3), 5 X 10(4), and 2.5 X 10(5) U. Daily observations of the animals showed a significant decrease of the incidence of new recurrent lesions with the use of 5 X 10(4) U of rIL-2 (rate of recurrence, 0.08, compared with 0.21 in untreated controls), whereas the other rIL-2 regimens did not affect the overall rate of recurrence. Weekly analysis of recurrences showed that treatment with 5 X 10(4) U of rIL-2 was effective only during the first 3 weeks of use and that 2.5 X 10(5) U of rIL-2 markedly decreased the rate of recurrence in the first week of treatment but not in subsequent weeks. The loss of clinical protection in both groups coincided with the production of neutralizing antibodies to rIL-2. The immune mechanisms possibly involved in the protective effect of rIL-2 in chronic HSV-2 disease were further investigated. Production of gamma interferon correlated well with clinical protection, and circulating levels dropped at the time when neutralizing antibodies to rIL-2 developed. Nonspecific cytotoxicity represented by natural killer cell and lymphokine-activated killer cell activities was also increased in the treated guinea pigs. Antibody titers and lymphocyte proliferation to herpes simplex antigen were similar in rIL-2 and placebo recipients. Finally, we found that the rIL-2-induced immune stimulation was as protective against recurrent HSV-2 disease in guinea pigs as the viral suppression achieved with acyclovir. However, the biological activity of both drugs was not additive when they were coadministered.

Acyclovir↗
PubMed1986

Regulation of guinea-pig immune functions by interleukin 2: critical role of natural killer activity in acute HSV-2 genital infection.

We have previously demonstrated that recombinant interleukin 2 (rIL 2) has a protective effect against acute HSV-2 infection in guinea pigs with a biphasic dose response which peaked between 4 and 20 X 10(4) U/kg, whereas 8 X 10(5) U/kg showed no effect on disease. Animals that escaped infection appeared lack immunologic memory to HSV-2, suggesting a nonspecific immune mechanism. In this study we have found that NK activity of fresh splenocytes measured against HSV-2 infected human foreskin fibroblast (HFF) is stimulated in vitro and in vivo by rIL 2 in a biphasic dose range similar to that determined for protection against disease. In contrast, lymphokine-activated killer (LAK)-mediated lysis of P815 showed a linear response to increasing concentrations of rIL 2 both in vitro and in vivo. Transfer of LAK cells did not alter the rate of infection after HSV-2 challenge. Anti-asialo GM-1 eliminated rIL 2 protection against HSV-2 infection. It also blocked HSV-2/HFF lysis and partially decreased P815 lysis in vitro; however, in vivo it inhibited both natural killer (NK) activity and LAK generation, failing to distinguish which of the lytic cells was responsible for the effect against infection. Early IgG production (7 days post-infection) was enhanced by rIL 2 administration before viral inoculation, but it did not influence the rate of infection as compared with controls. Polyclonal IgM secretion was not found to play a role in acute protection. Circulating serum interferon levels were enhanced with increasing concentrations of rIL 2 but did not correlate with the biphasic dose curve for protection. Therefore of these mechanisms the one that is most closely related to the protective effect of rIL 2 against primary HSV-2 infection appears to be NK-mediated lysis, although the other mechanisms may add to this effect.

Animals↗
PubMed1986

Synergistic antitumor effect of interferon and anti-idiotype monoclonal antibody in murine lymphoma.

Both IFN-alpha and anti-idiotype monoclonal antibody therapy have significant antitumor activity in vivo in a murine B cell lymphoma model. Combination therapy with syngeneic anti-idiotype antibody of the IgG2a or IgG2b isotype (a single i.p. injection of 100 micrograms) and recombinant human hybrid interferon-alpha A/D (10(4) to 10(6) U three times weekly for 3 wk) synergistically increased median survival time in mice challenged with a lethal dose of tumor cells compared with the sum of the median survival times of the two individual treatments. IFN-alpha has direct antiproliferative activity against 38C13 in vitro and enhances in vitro macrophage anti-idiotype antibody-specific cytolysis for IgG2a, IgG2b, and IgG1 isotypes.

Animals↗
PubMed1986

Acute genital infection in guinea pigs: effect of recombinant interleukin-2 on herpes simplex virus type 2.

Human recombinant interleukin-2 (rIL-2) modifies infection with herpes simplex virus type 2 (HSV-2) in normal guinea pigs. Animals were injected sc with rIL-2 twice a day, beginning 24 hr before infection and continuing for three subsequent days. Guinea pigs were assigned to five different regimens in which rIL-2 was administered daily at dosages from 8 X 10(3) U/kg to 8 X 10(5) U/kg. After intravaginal inoculation with HSV-2, 83% of 24 control animals developed apparent genital herpes, and 5% had asymptomatic viral shedding. Animals receiving 4 X 10(4) U or 2 X 10(5) U or rIL-2/kg showed a significantly lower rate of infection (P less than .001 by chi 2) and a lower number of lesions and more rapid healing than did the infected animals in the control (untreated) group. The mortality in the untreated group (28%) was higher than in the animals in the 2 X 10(5) U/kg treatment group (7%). No difference was observed between the control, the 8 X 10(3) U/kg, and the 8 X 10(5) U/kg treatment groups with respect to severity of infection or mortality. Animals examined two to four weeks after inoculation had lymphocyte stimulation indices (induced with HSV-2 antigen) greater than 3.5 and titers of antibody between 2.5 log10 and 4.5 log10 by radioimmunoassay. In the disease-free animals, stimulation indexes were less than 2 and antibodies were undetectable. The mean stimulation index was 54 +/- 16 in the diseased control animals and 12 +/- 7 (P less than .05) in the 2 X 10(5) U/kg treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Human keratinocyte-lymphocyte reactions in vitro.

To extend our observation that recombinant gamma interferon (r-IFN-gamma) induces the synthesis and expression of HLA-DR antigen we have investigated 2 major areas including the modulation of r-IFN-gamma-induced HLA-DR expression and the possible immunologic consequences of keratinocyte HLA-DR expression in vitro. The induction of keratinocyte HLA-DR expression was greater for continuous compared with pulse dosage (0.5-24 h) of r-IFN-gamma and was markedly decreased after trypsinization of attached monolayers into single cell suspensions. The r-IFN-gamma caused induction of HLA-DR and this was not influenced by either pretreatment with irradiation, PGE2, or indomethacin. Both HLA-DR+ and HLA-DR- cultured keratinocytes induced RNA synthesis and gamma interferon production by allogeneic peripheral blood mononuclear leukocytes (PBMLs) indicating mononuclear cell activation. However, this activation was not followed by significant mitogenesis and only slightly increased levels of [3H]thymidine incorporation (maximal = 5800 cpm) by the PBMLs was observed. Cultured keratinocytes apparently inhibit both lectin-driven and mixed-lymphocyte reactions by producing a soluble mediator which is not dialyzable, or inhibited by pretreatment with indomethacin or anti-alpha, -beta, -gamma interferon antibodies. These results suggest that lymphocyte-keratinocyte reactions in vitro are complex and may be mediated by a variety of cytokines, lymphokines, and prostaglandins.

Cell Division↗
PubMed1986

Preliminary trial of recombinant fibroblast interferon in chronic hepatitis B virus infection.

Five patients with chronic hepatitis B were treated with 8-day courses of leukocyte (alpha) interferon (5 X 10(6) U/day) and with 8-day courses of recombinant fibroblast (betaser) interferon at dosages of 5 X 10(6), 35 X 10(6), and 105 X 10(6) U/day. Inhibition of hepatitis B virus replication as evidenced by a decrease in DNA polymerase (DNAP) activity was seen during all treatment courses. Equivalent reduction in DNAP was seen from the low-dose alpha and beta ser regimens, but beta ser interferon at 35 X 10(6) U/day achieved a significantly greater decrease in DNAP activity than did the low-dose regimens. In no patient, however, was permanent loss of DNAP noted. Because of dose-limiting toxicity, only two patients were escalated to the 105 X 10(6)-U/day dosage level. Transient proteinuria was noted in two patients while they were receiving interferon. This has not been noted in other patients receiving this preparation and could not be explained by the development of anti-interferon antibodies. This study has defined an appropriate dosage for future longer-term trials of this agent alone and in combination with other antivirals for the treatment of chronic hepatitis B.

Adult↗
PubMed1986

Cervical intraepithelial neoplasia treated by perilesional injection of interferon.

Twelve patients with cervical intraepithelial neoplasia (CIN) were studied by colposcopy and cervical smears to elucidate the local response to interferon alpha and beta given by perilesional injections and to assess long-term disease remission. In all patients, local inflammatory response was seen and persisted throughout the treatment period. Selective toxic effect was evident by exfoliation of increasing proportion of degenerate to viable dyskaryotic cells, while the normal epithelial cells appeared unaffected, and by the progressive regression of the lesion. Interferon alpha induced complete remission in six of seven (85.7%) patients but three had recurrence 12 to 24 months later, while interferon beta induced complete remission in only two of five (40%) patients.

Colposcopy↗
PubMed1985

Human interferon alpha in malignant lymphoma and Hodgkin's disease. Results of the American Cancer Society trial.

Forty-nine patients with non-Hodgkin's lymphoma or Hodgkin's disease were entered into a multi-institutional phase II trial to evaluate the antitumor activity of human interferon alpha, prepared from buffy coats. Interferon alpha was administered intramuscularly in doses of 1 X 10(6) u, 3 X 10(6) u or 9 X 10(6) u daily for 30 days. Objective partial responses were seen in 3 of 18 patients with nodular lymphoma, all at the 9 X 10(6) u dose. Interferon alpha was not observed to be of therapeutic benefit in the other subtypes of non-Hodgkin's lymphoma or Hodgkin's disease. The major toxicities consisted of fatigue, fever, myalgias and weight loss. Serum interferon levels obtained 3 to 4 hours after injection varied widely, even among patients treated at the same dose level. Despite the relatively low doses of interferon used and the brief period of administration, this study extends the earlier observations of the antitumor effect of interferon in nodular lymphoma. These results are discussed in relation to the cumulative experience in human lymphoma using alpha interferons induced in human leukocytes and those produced in bacteria by recombinant DNA techniques.

Adolescent↗
PubMed1985

Serial immunological studies in multiple sclerosis patients treated systemically with human alpha interferon.

A battery of immunological functions was studied over a 2-year period in conjunction with a placebo-controlled trial of natural human alpha interferon in patients with multiple sclerosis. IgG synthesis was increased both systemically and intrathecally by administration of interferon; however, there were only minor changes in cerebrospinal fluid oligoclonal bands. Levels of helper and suppressor T lymphocytes fluctuated independently of clinical exacerbations, although mean helper/suppressor ratios were higher in multiple sclerosis patients than in controls and increased further during interferon treatment. Cerebrospinal fluid myelin basic protein and antibodies to basic protein were not affected by exacerbations or by interferon administration. Circulating IgG antibodies induced by interferon treatment appeared to be directed at a non-interferon contaminant of the preparation. None of the assays was a consistent indicator of disease activity or of clinical response to interferon.

Adult↗
PubMed1985

Immunological complications in multiple sclerosis patients receiving interferon.

In a prospective, placebo-controlled study designed to test the efficacy of human alpha interferon (IFN) in the treatment of multiple sclerosis, we monitored several immunological functions. Interferon was shown to have many effects on the immune system, including activation of natural killer cells in vivo and elevation of serum immunoglobulin and cerebrospinal fluid IgG ratios. Furthermore, all patients who received IFN developed antibody titers to a protein contaminant (molecular weight, 27 kilodaltons) in the IFN preparation. This antibody was associated with an elevation in serum concentrations of C1q- and Raji-binding immune complexes in 6 of 12 patients. Some of these 12 patients developed symptoms suggestive of immune complex disease. IFN had pronounced effects on the immune system of these patients.

Antibodies↗
PubMed1985

Transfusion-acquired cytomegalovirus infection in cardiac surgery patients.

The incidence of transfusion-acquired primary cytomegalovirus (CMV) infection was studied in 483 cardiac surgery patients. Ninety-six patients (20%) were found to lack antibody to CMV [CMV Ab(-)] as measured by radioimmunoassay. Sixty-eight CMV Ab(-) were followed by viral culture and/or serology from eight weeks to one year after transfusion. Transfusion requirements in CMV Ab(-) patients were as follows: whole blood/packed red blood cells, mean 4.7 +/- 2.6 units; platelets (20 patients), 6.9 +/- 3.8 units; fresh frozen plasma (25 patients), mean 3.3 +/- 1.6 units. Forty-nine percent of 235 donor units tested had antibody to CMV. One donor unit (0.4%) had CMV-specific IgM. This was not associated with CMV infection in the recipient. One patient (1.5%) demonstrated evidence of seroconversion to CMV during the follow-up period. This is significantly less than reported in previously published studies (P less than .01). Serological methods used, the age of the transfused blood, the immune status of the transfusion recipient, and the administration of passive antibody in fresh frozen plasma are factors that may be responsible for the low incidence observed.

Antibodies, Viral↗
PubMed1985

Human cytomegalovirus polypeptides stimulate neutralizing antibody in vivo.

At least three human cytomegalovirus polypeptides are targets for virus neutralizing antibody; a single protein of 86,000 molecular weight (p86) and two coimmunoprecipitating proteins of 130,000 and 55,000 molecular weight (p130/55). These polypeptides have been isolated by immunoaffinity chromatography and tested for immunogenicity in guinea pigs. Neutralizing antibody was detected after immunization with both p86 and p130/55. Hyperimmune sera to p130/55, but not p86, were dependent upon guinea pig complement for virus neutralization.

Animals↗
PubMed1985

Recombinant gamma interferon differentially regulates class II antigen expression and biosynthesis on cultured normal human keratinocytes.

Recombinant gamma interferon induces class II antigen (HLA-DR) biosynthesis and expression on normal cultured human keratinocytes. HLA-DR expression was not induced on keratinocytes by recombinant alpha or beta interferons in a similar dose range nor by Con A or PHA. HLA-DR (L243) expression, as determined by FACS analysis, was detected as early as 1-2 days after addition of r-IFN-gamma to the cultures and was maximal after 4-8 days. Keratinocytes were analyzed for expression of another class II antigen, HLA-DC (Leu-10). Little or no expression of Leu-10 (DC) was detectable on these cells although Fc receptors for the IgG1 isotype were increased. These data indicate a unique role for gamma interferon in the differential regulation of keratinocyte class II antigen biosynthesis and expression. Induction of HLA-DR on keratinocytes may be functionally important in expanding the number of antigen presenting cells in the skin for the induction of an immune response and/or targeting these keratinocytes for cytolysis.

Cells, Cultured↗
PubMed1985

Role of macrophage D-region antigens and T-lymphocyte differentiation antigens in induction of gamma interferon.

Macrophage-T-lymphocyte cultures from patients with recent recurrent herpes labialis were stimulated to produce gamma interferon by either herpes simplex antigen or mitogens (PHA and Con A). The ability of monoclonal antibodies to HLA-DR and DC/DS, HSV glycoprotein antigens and T-lymphocyte surface antigens to inhibit interferon production and lymphocyte proliferation were studied. Anti-D region antibodies inhibited HSV antigen-induced but not mitogen-induced interferon and proliferation. The extent of inhibition varied mainly according to the determinants recognized by the antibodies and, to a lesser degree, between patients. Inhibition probably resulted from inhibition of antigen presentation, through antibody binding to macrophage D-region antigens. Interferon production was a more sensitive index of inhibition than lymphocyte proliferation. With one antibody (L227) a marked difference in inhibition in the two assays was noted, suggesting that lymphocytes producing gamma interferon may differ from the majority of the proliferating cells in their recognition of D-region determinants. Antibodies to the HSV glycoprotein antigens (gA/B, gC, gD, gE) did not produce consistent significant inhibition of interferon production and had no effect on proliferation. Anti-Leu 4 and -Leu 5 inhibited HSV antigen and mitogen induction of gamma interferon (and proliferation). Anti-Leu 2 and anti-Leu 3, mildly inhibitory alone, produced synergistic inhibition together. Hence, in human systems, the interaction between macrophages and T lymphocytes in producing gamma interferon appears to differ according to mode of induction. Macrophage D-region antigens are required for antigen induction probably via presentation whereas other factor(s), probably monokine secretion, are necessary for mitogen induction. Antibodies acting on the T-lymphocyte surface appear to affect a final common pathway of interferon induction, similar to their effects on proliferation and secretion of other lymphokines.

Antibodies, Monoclonal↗
PubMed1985

Interferon gamma production by herpes simplex virus antigen-specific T cell clones from patients with recurrent herpes labialis.

Nineteen herpes simplex virus (HSV) antigen-specific human T lymphocyte clones were established from three volunteers with recent recurrent herpes labialis. All produced interferon gamma (IFN-gamma) at titres of 200 to 700 units/ml when cultured in vitro with HSV antigen and irradiated peripheral blood mononuclear cells (PBMC) as filler cells. All 10 of those clones whose phenotype was determined were Leu 4+, Leu 2-, Leu 3+. Interleukin 2 alone failed to induce IFN-gamma in titres greater than 10 units/ml from these clones cultured at 10(4)/0.2 ml/well. However, the effect of different accessory or filler cells on IFN-gamma production by clones was quite marked. For example, high titres were produced when irradiated PBMC or plastic-adherent cells (predominantly monocytes) were added and low titres when macrophages and irradiated Epstein-Barr virus-transformed B (EBV-B) cells were added. When tested for HSV antigen-stimulated IFN production alone, the irradiated PBMC and adherent cells produced low titres, but no detectable interferon was produced by the others. However, with higher concentrations of EBV-B cells, low concentrations of IFN-alpha were occasionally produced. Irradiation strikingly reduced IFN-alpha-production by PBMC. The IFN-alpha and -gamma produced by accessory cells may contribute to total IFN production by priming the production by cloned cells, and acting in synergy with IFN-gamma produced by the cloned cells. Alternatively, the effect may be due to the presence of permissive concentrations of other lymphokines such as the interleukins. Interferon production by cloned T lymphocytes in the presence of non-producing macrophages was maximal within 24 h, much faster than with a similar polyclonal system, although attaining lower titres. EBV-B cells from only one of three patients supported antigen-specific lymphocyte activation. Almost all cells of the three cell lines expressed DR antigens, while DS/DC antigens were also expressed on nearly all cells of the antigen-presenting line and, at lower densities, on two-thirds of the cells of the other two lines.

Antigen-Presenting Cells↗