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Biomedical subjects

T C Merigan

Publications and source records attributed to T C Merigan.

At least 199 records · Page 11Linked to original sources
PubMed1984

Antiproliferative effects of recombinant alpha- and gamma-interferons on cultured human keratinocytes.

To extend our initial observation that recombinant gamma-interferon induced expression of class II major histocompatibility (HLA-DR) antigen on normal cultured human keratinocytes, we studied the antiproliferative effects of recombinant alpha- and gamma-interferons. Both interferons reduced the number of attached cells (dose range 10-10(3) units/ml; 7.1 X 10(-11) to 7.1 X 10(-9) M) and gamma-interferon was 100 times more potent than alpha. This effect did not require the presence of Langerhans cells. gamma-Interferon reduced total cell production during the first week without increasing the percentage of cells shed. During the second week, gamma-interferon also increased the percentage of cell shedding. Although 10(2) units/ml of gamma-interferon was maximal for HLA-DR expression by cultured keratinocytes, there was increasing reduction of attached cells between 10(2) to 10(3) units/ml. The demonstration that recombinant gamma-interferon induces HLA-DR expression and also inhibits keratinocyte proliferation in vitro at nanomolar concentration expands the growing list of normal cells whose biologic function may be influenced by this lymphokine in vivo.

Cell Count↗
PubMed1984

Leu-3+ T cells produce gamma-interferon in patients with recurrent herpes labialis.

Interferon-gamma (IFN-gamma) was spontaneously secreted by peripheral blood mononuclear cells cultured from patients soon after recurrent herpes labialis (RHL) or was induced from macrophage-T lymphocyte cultures in vitro with HSV antigen. Circulating Leu-3+/Leu-2- cells produced the spontaneous IFN almost exclusively. In the HSV antigen-stimulated culture system the same subset was the predominant producer of IFN-gamma. The IFN-gamma producing leu-3+ lymphocytes were plastic nonaderent but nylon wool adherent, and may be analagous to the murine Th 2 helper cell. In contrast to one lymphocyte subset being the major IFN-gamma producer in this viral disease, mitogen stimulation induced IFN-gamma from all (Leu-2+/2- and Leu-3+/3-) subsets, with panning as the separation technique. As mitogens circumvent the normal processing and presentation of antigen, the RHL system described above may provide a more accurate picture of the relative contributions of helper (Leu-3+) and cytotoxic/suppressor (Leu-2+) T cells to IFN-gamma production in herpes viral disease.

Antibodies, Monoclonal↗
PubMed1983

Rapid detection and quantitation of human cytomegalovirus in urine through DNA hybridization.

We detected cytomegalovirus DNA in clinical urine specimens after immobilization on nitrocellulose filters and hybridization with a radioactively labeled, cloned fragment of cytomegalovirus DNA. We accomplished the specific detection and quantitation of viral DNA within 24 hours with 39 urine specimens from nine patients with cytomegalovirus viruria, mostly at a tissue-culture infective titer of 10(3) per milliliter or higher. None of 57 urine specimens from 21 patients that were culture-negative for cytomegalovirus gave false-positive results. Analysis of specimens from patients with cytomegalovirus viruria showed a correlation of the infective titer with the intensity of DNA hybridization (r = 0.77). Hybridization of sequential urine specimens from a patient undergoing treatment with interferon for cytomegalovirus retinitis revealed quantitative variations in hybridizable viral DNA over a period that correlated with clinical findings. This assay can be useful in the selection of patients for antiviral therapy and for the assessment of its efficacy.

Cytomegalovirus↗
PubMed1983

Natural killer cell activity in patients with multiple sclerosis given alpha interferon.

The purpose of this study was to examine the function and regulation of natural killer cells in vitro and in vivo in patients with multiple sclerosis. Of 12 patients who received 5 X 10(6) international units of human alpha interferon, 9 demonstrated an increase in natural killer cell activity within 48 hours as defined by the lysis of 51Cr-labeled K-562 cells. The activity was normal before treatment, unlike that of tumor-bearing patients, and reached baseline levels within one week despite continuous interferon administration over the next six months. The same patients given a placebo preparation failed to show this enhanced natural killer cell activity. We also studied K-562 killing in 36 other patients and age- and sex-matched control subjects and were unable to demonstrate any differences between the two groups or any correlation of natural killer cell function with disease activity. The in vitro augmentation of natural killer cell activity by purified measles virions, which is associated with the release of interferon, and by the isolated glycoproteins of measles virus, which activates natural killer cells without the extracellular release of interferon, was similar in both patients and control subjects. Further, the proportion of cells defined by the monoclonal antibody HNK-1, which defines both natural killer cells and a small subset of cytotoxic T lymphocytes, was normal. In patients with multiple sclerosis, the normality of natural killer cell function, as defined by these several interrelated assays, speaks against a defect in this nonspecific antiviral defense mechanism in the pathogenesis of the disease.

Adult↗
PubMed1983

Interferon prophylaxis against simian varicella in Erythrocebus patas monkeys.

Erythrocebus patas monkeys were given placebo or human leukocyte interferon (5 x 10(5) units/kg of body weight per day im) for five days during an epizootic of simian varicella. During the 14 days beginning with the first day of treatment, the attack rate for simian varicella was 14.3% (two of 14) among interferon recipients compared to 70% (nine of 13) among placebo recipients (P less than 0.025). Excluding animals with antibody to simian varicella when the study began, 18% (two) of 11 interferon recipients had symptoms of infection compared to 80% (nine) of 11 placebo recipients (P less than 0.025). The epizootic began in a room housing male animals. The incidence of infection in male placebo recipients was 100% (seven of seven) compared to 14% (one of seven) in male interferon recipients (P less than 0.01). The efficacy of interferon prophylaxis in the simian varicella model supports its continued evaluation for the management of human varicella in high-risk patients.

Animals↗
PubMed1983

Infections due to herpesviruses in cardiac transplant recipients: role of the donor heart and immunosuppressive therapy.

The role of the donor heart and immunosuppressive therapy on infection due to herpesviruses in 74 cardiac transplant recipients (CTRs) was determined. When cellular blood products from donors seronegative for antibody to cytomegalovirus (anti-CMV) were used, all primary CMV infections were attributable to transmission from donor heart. None of eight CTRs negative for anti-CMV before transplant and who received an anti-CMV donor heart and anti-CMV blood products developed CMV infection compared to one (20%) of five who received unscreened blood. A change from high-dosage anti-thymocyte globulin, azothioprine, and prednisone (ATG regimen) to low-dosage anti-thymocyte globulin, cyclosporin A, and prednisone (CsA regimen) significantly decreased the severity and prevalence of lesions due to herpes simplex virus and the duration of CMV shedding in patients with recurrent CMV infection. CTRs with recurrent CMV infection treated with the ATG regimen had significantly more fever, required more parenteral antibiotics, and were more likely to be infected with opportunistic pathogens than were CsA-treated patients.

Antibodies, Viral↗
PubMed1983

Acute Dane particle suppression with recombinant leukocyte A interferon in chronic hepatitis B virus infection.

The clinical, virologic, biochemical, and immunologic effects of a biosynthetic human leukocyte interferon, recombinant leukocyte A interferon (rIFN-A or HuIFN-alpha 2) are reported in nine patients with chronic hepatitis B virus infection and circulating Dane particle-associated polymerase activity. Eight-day courses of rIFN-A were given starting at a dose of 3 X 10(6) units per day and reaching 68 X 10(6) units per day in two patients. Major toxic side effects included fever, fatigue, gastrointestinal symptoms, myalgias, and headache. Most courses of rIFN-A were associated with a reduction in Dane particle-associated polymerase activity, but in no case was this change permanent. There were also changes in lymphocyte subpopulations at the higher dosage levels of rIFN-A. Because of the reproducible, statistically significant effect on viral replication, further study with this and other biosynthetic interferon species is warranted.

Adult↗
PubMed1983

Growth regulation of melanoma cells by interferon and (2'-5')oligoadenylate synthetase.

We report that endogenous, as well as exogenous, interferon (IFN) regulates the growth of human melanoma cells in culture. When antibodies directed against human fibroblast IFN were incorporated into the media of high-density cells stimulated to proliferate with serum, the cells entered the cell cycle earlier than did the controls. In investigating the biochemical basis for this finding, we have found that there is an inverse relationship between the (2'-5')oligoadenylate synthetase levels and the percentage of cells in S in untreated cultures. Upon IFN treatment, the relationship is obliterated and (2'-5')oligoadenylate synthetase levels increase throughout all phases of the cell cycle. This increase in enzyme levels correlates well with the decreased probability of the IFN-treated cells to cycle. These findings suggest a biological role for IFN as a negative growth factor for cells in culture.

2',5'-Oligoadenylate Synthetase↗
PubMed1983

Phase I study of human leukocyte interferon in patients with advanced cancer.

Seventeen patients with disseminated cancer were treated with a human leukocyte interferon preparation in doses ranging from 3 X 10(6) to 50 X 10(6) IU daily for 30 days. Doses above 18 X 10(6) IU were considered intolerable in this schedule of administration due to severe fatigue and weight loss. Serum concentrations of interferon were lower than those achieved with either partially pure native or recombinant leukocyte interferon. Three of 17 patients in this study showed minimal evidence of tumor regression. Two patients treated at doses of 18 X 10(6), 36 X 10(6), and 50 X 10(6) IU also received a 5 X 10(6)-IU dose of a second human leukocyte interferon preparation. The latter resulted in less toxicity but similar serum levels. These results suggest that human leukocyte interferons prepared in the same manner may differ significantly in their in vivo biologic properties.

Adult↗
PubMed1983

Recombinant interferon-gamma increases HLA-DR synthesis and expression.

It has been shown that all three classes of interferons enhance the expression of the major histocompatibility class I antigens (HLA-A,B,C;H-2) on a wide variety of cell types (1-10). However, their effect on the expression of the class II antigens (HLA-DR, Ia), which play a major part in cellular interactions that initiate an immune response, is more controversial. The predominate findings have been that the interferons specifically increase the synthesis and expression of only the class I antigens (3, 4, 6, 8, 10, 11). We report here that recombinant interferon-gamma (IFN-gamma) increases the synthesis and expression of the HLA-DR (la-like) antigens as well as beta 2-microglobulin (beta 2-m), a low m.w. subunit of HLA, on human melanoma cells. No increase in HLA-DR was detected on these melanoma cells with leukocyte interferon (IFN-alpha) at doses 400 times higher than the maximum dose of IFN-gamma. These findings were extended to show that pure IFN-gamma also increases the expression of the HLA-DR antigens on normal peripheral blood monocytes, whereas recombinant IFN-alpha at a similar dose had little effect on the expression of this surface antigen. These findings suggest a specialized role for IFN-gamma in immune regulation in comparison with IFN-alpha.

Glycoproteins↗
PubMed1983

gamma Interferon production appears to predict time of recurrence of herpes labialis.

Peripheral blood mononuclear cells separated from the blood of 29 volunteers within 3 wk of the onset of recurrent oral herpes labialis spontaneously secreted IFN-gamma (and small amounts of IFN-beta) into the culture medium in varying amounts (mean = 77 U/ml, SE = 17). However, interferon could not be detected in the serum of 10 of these patients tested. In the group as a whole, peak levels of interferon were secreted in vitro at 6 to 20 days after the onset of herpes labialis. Serial studies in eight patients showed peak production in the second or third week, with subsequent decrease to undetectable levels at 6 wk. A strong correlation between peak supernatant interferon level and the time to the next recurrence of herpes labialis in each patient was noted (r = 0.82, p less than 0.0001). Herpes simplex antigen-stimulated mononuclear cell cultures from each patient produced a mixture of IFN-alpha and IFN-gamma. A less marked but still significant correlation was noted between the peak mixed interferon level and the inter-recurrence interval (r = 0.52, p less than 0.005). These results suggest that a recurrent herpes labialis acts as an in vivo stimulus to the induction of IFN-gamma-producing cells that circulate in peripheral blood. The IFN-gamma produced is either a direct determinant of frequency of recurrence of herpes or a quantitative marker for other cellular immune events determining frequency.

Female↗
PubMed1982

Interferons as antivirals in man.

Interferons have now been used in both prophylaxis and treatment of a number of human viral infections. The major action has been as a prophylactic for sites within the body that are not yet involved by disease. Such a prophylactic effect can be obtained early in the treatment of acute viral infection or even during chronic viral disease. Both local and systemic prophylaxis have been achieved with regard to both respiratory and herpesviral illness. In addition, Dane particle suppression can be achieved consistently with dosages of 10(6) units or greater daily to patients with chronic hepatitis B virus infection. In certain cases with prolonged therapy there can be permanent eradication. With leucocyte-derived material of approximately 10(6) or 10(7) units per milligram protein, the major side effects have been an initial febrile response, fatigue, malaise, marrow suppression, and inhibition of hair growth. So far, side effects have been rapidly reversible on lowering of dosage. Present studies with the use of lymphoblastoid interferon and bacterial-derived interferon employ materials of significantly greater specific activity. Such experience suggests that the same general side effects that were limiting with leucocyte interferon are present with interferon produced from recombinant DNA by bacterial as well as with lymphoblastoid interferon.

Antiviral Agents↗
PubMed1982

Preliminary studies of acyclovir in chronic hepatitis B.

Three patients with HBsAg-positive and DNA-polymerase-positive chronic hepatitis were treated with increasing dosages of intravenous acyclovir. A fall in DNA polymerase activity was seen with all courses of acyclovir but no dose-response relationship was evident. In only one patient did DNA polymerase fall to zero where it has remained for five months. Two out of 10 courses were associated with significant side effects with the highest dosages of acyclovir but these promptly resolved when the agent was stopped. Acyclovir's apparently partial and transient action suggests that it will not have a role in the treatment of chronic hepatitis B virus infection.

Acyclovir↗
PubMed1982

Vidarabine monophosphate and human leukocyte interferon in chronic hepatitis B infection.

Ten young adult patients with chronic hepatitis B virus infection and positive hepatitis B e antigen and DNA polymerase (DNAP) levels were treated with alternating courses of seven to 28 days of 5 to 7.5 mg/kg of vidarabine monophosphate (adenine arabinoside monophosphate) and 28 days of human leukocyte interferon (IFN-alpha); three different regimens were given on an outpatient basis. All patients with a fall in their DNAP level, and the DNAP remained undetectable six months after treatment was stopped in one patient. The major side effect, which most often occurred in those patients receiving 7.5 mg/kg of vidarabine monophosphate, was severe muscular pains. This study demonstrated the feasibility of administering vidarabine monophosphate and interferon to outpatients. Based on data from this and other studies, it is now possible to use a relatively nontoxic regimen that includes 28 days of 5 mg/kg of vidarabine monophosphate in a larger controlled study to answer the question of efficacy.

Adult↗