Effects of Adenine Arabinoside on Cellular Immune Mechanisms in Humans

Steele, Russell W.; Chapa, Isidoro A.; Vincent, Monroe M.; Hensen, Sally A.; Keeney, Ronald E.

doi:10.1128/aac.7.2.203

Cited by 52 publications

(3 citation statements)

References 9 publications

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“…The two other compounds investigated in the present communication, Ara-A and Ara-C, were far more toxic to lymphocyte function than was OCH3CH2UdR. Our observation that a dose of 4 ,g of Ara-A per ml was not toxic agrees favorably with the work of Steele et al (23). Also in concurrence with their work, Ara-C was shown to be markedly more suppressive to lymphoid function than was Ara-A.…”

Section: Discussionsupporting

confidence: 91%

Effect of anti-herpesvirus drugs on human and bovine lymphoid function in vitro

Babiuk¹,

Rouse²

1975

Infect Immun

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Lymphocyte proliferative responses to phytohemagglutinin, pokeweed mitogen, and herpesvirus (herpes simplex virus and infectious bovine rhinotracheitis virus) antigens were evaluated in the presence of various concentrations of the anti-herpesvirus drugs, methylmethoxydeoxyuridine (OCH3CH2UdR), cytosine arabinoside was inhibitory at 25 ug/ml and cytosine arabinoside was inhibitory OCH3CH2UdR per ml, lymphocyte proliferative responses were unaffected and were not abolished even by concentrations of 2,500 ,Lg/ml. In contrast, adenine arabinocide was inhibitory at 25 ,.g/ml and cytosine arabinoside was inhibitory at 5 ,ug/ml. Both direct and antibody-dependent lymphocyte cytotoxicity of herpesvirus-infected target cells were highly resistant to OCH3CH2UdR; concentrations of 1,000 ,ig/ml were only marginally inhibitory. The anti-herpesvirus activity of all three drugs is similar (0.5 to 8 ug/ml) (L. A. Babiuk, B. Meldrum, V. S. Gupta, and B. T. Rouse, submitted for publication). The drug OCH3CH2UdR should be given a careful, well-controlled evaluation of its effectiveness in the treatment of herpes simplex infections in animals, perhaps including humans, since our results using in vitro models show that cellular responses important for recovery from herpesvirus infections are unaffected by doses far in excess of those found to be antiviral.

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Section: Discussionsupporting

confidence: 91%

Effect of anti-herpesvirus drugs on human and bovine lymphoid function in vitro

Babiuk¹,

Rouse²

1975

Infect Immun

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“…The rapid drop in leukocyte and lymphocyte counts and the number of Ficoll-Hypaque gradient cells observed in patients receiving Ara-A may relate to the toxicity of Ara-A to mononuclear cells observed in vitro. Despite the in vitro and in vivo toxicity of Ara-A, the results of this study are in agreement with the findings of Steele et al (23) in that there was no interference with cellular immune response as measured by the LT assay as long as a sufficient number of mononuclear cells were exposed to antigen. Since successful antiviral therapy appears to require the cooperation of host immune responses (T. C. Merigan, in B. Amos, ed., The Interface Between Immune Mechanism and Disease, in press), it is possible that the lymphopenia and suppression of immune response caused by HLI treatment, and the depletion of circulating lymphocytes seen in patients treated with large doses of Ara-A, might interfere with optimal treatment results.…”

Section: Discussion the Viability Of Mononuclear Cells In Cellsupporting

confidence: 82%

Effects of Interferon and Adenine Arabinoside Treatment of Hepatitis B Virus Infection on Cellular Immune Responses

Hafkin

Pollard

Tiku

et al. 1979

Antimicrob Agents Chemother

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Fifteen patients with chronic hepatitis B were treated with adenine arabinoside (Ara-A) or human leukocyte interferon (HLI). Cellular immune response to hepatitis B virus surface antigen and antigens prepared from herpes simplex virus, varicella zoster virus, and cytomegalovirus was measured by a lymphocyte blast transfornation assay and an assay for interferon production. Measurements were made before, during, and after antiviral treatment. Unlike patients convalescing from acute hepatitis B, only 2 of 15 patients with chronic hepatitis B had significant blast transformation to hepatitis B surface antigen. One such response occurred during the pretreatment period of HLI therapy, and the other was in a patient undergoing low-dose (<105 U/kg per day) HLI therapy. Mononuclear cell cultures were tested for interferon production in the presence of hepatitis B surface antigen. Cells from only 1 of 15 patients produced detectable levels of interferon. In contrast, all of these patients had normal cellular immune responses to herpesvirus antigens. Transformation responses to herpes antigens decreased three-to fivefold after patients were treated with >iO5 U of HLI per kg per day.Antiviral therapy with <105 U of HLI per kg per day or Ara-A did not produce a detectable depression of transformation response. Ara-A produced marked lymphocytopenia and a marked lymphocyte fragility after 5 or more days of therapy. In vitro Ara-A was toxic to lymphocytes at concentrations as low as 0.5 pg/ml. These changes in lymphocyte parameters may affect the outcome of antiviral therapy.In preliminary trials of human leukocyte interferon (HLI) and adenine arabinoside (Ara-A) administration in chronic hepatitis B virus (HBV) infection (CH/HB5Ag+), variable therapeutic responses were observed. Although some patients with CH/HB6Ag+ experienced rapid and prolonged depression of HBV markers such as Dane particle-associated deoxyribonucleic acid polymerase, others with apparently similar disease states (as measured by physical examination, HBV markers, and liver function tests) had less depression of HBV markers; these changes were observed only during therapy (12,21). Ara-A and HLI might influence immune cell function adversely and thereby produce the less durable antiviral response observed in some patients. Altematively, changes in immunity may occur only in certain patients and may not be a universal response.To

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“…Secondly, the infected mastocytoma cell was, in our system, just as lysable as the L cells under the prerequisite that the syngeneic cytolytic effector cell was used. Other investigators communicated virus-specific lysis of heterologous infected target cells [5,10,111. For these systems the T cell specificity of the reaction has t o be elucidated t o exclude antibody-dependent activities [34-371.…”

Section: Effect Of Target Cell Specificity On Virus-specific Lymphocymentioning

confidence: 99%

Target cell‐dependent T cell‐mediated lysis of vaccinia virus‐infected cells

Koszinowski¹,

Thomssen²

1975

Eur J Immunol

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Cell-mediated lysis of virus-infected cells 245are at work f o r cellular antigens also. This confirms their im- Elimination of B cells was performed by incubation with goat antiserum to mouse Ig (Gibco, BCL 1039). The serum was absorbed with C3H mouse thymocytes until there was no more cytotoxicity against thymocytes. 15 x 1 O6 cells were incubated in 0.2 ml of antiserum 30 min in 37 "C, washed and incubated again with an equal volume of guinea pig complement absorbed with mouse liver powder. T cell eliminationAnti-@ serum from AKR mice was kindly provided by Dr.Rollinghoff, Mainz. 1 5 x l o 6 spleen cells were incubated in 0.2 ml anti-@ serum for 30 min at 37 "C. Controls were run with normal mouse serum. The cells were washed and resuspended in 0.2 ml guinea pig complement absorbed with mouse liver powder and agarose [ 201. After incubation for 30 min at 37 "C the cells were washed and resuspended to the desired concentration. The viability of the cells was tested by the trypan blue exclusion test. Anti-vaccinia serumHyperimmune serum was obtained from sensitized rabbits injected intracutaneously with 5 ml 1 O6 TCIDso/ml followed 6-10 weeks later by booster intravenous injections of the same dosage. Syngeneic hyperimmune serum was obtained from mice after three intraperitoneal injections of 2 ml 1 O6 TCIDso/ml given at two week intervals. The animals were bled one week after the last injection. Normal serum was obtained from noninfected animals. All sera were inactivated and stored at -70 "C. Target cellsL-929 cells, kindly provided by Dr. Lehmann-Grube, Hamburg, were grown as monolayers in MEM containing 10 % FCS and 100 pg/ml of penicillin and streptomycin in Roux bottles. Mastocytoma P-8 15-X2 suspension cultures were grown in 10 cm Petri dishes containing Dulbecco's fortified Eagle's medium (Grand Island Biological Co.) with 10 % FCS and antibiotics, on a rocker platform (Bellco Glass Co, Vineland, N.Y.) in a humidified 8 % C02-atmosphere. Infection of target cellsMonolayers of L-929 cells were trypsinized, suspended in fresh medium and plated in 0.1 ml volumes in sterile flat bottom microtest plates (Greiner, Nurtingen N o 220 ART)t o reach a final concentration of 5 x 1 O4 cells/well. Five hours later the medium was removed and the cells were incubated with 0.2 ml virus suspension containing 5 x 1 O5 TCIDso/ 0.2 ml medium. Two hours later all the supernatants were discarded and fresh medium was added. Suspensions of mastocytoma P-815-X2 cells were infected by incubating the cells in a medium containing 10 TCIDSO of virus per mastocytoma cell under constant rocking. After 2 h the cells were washed and resuspended in fresh medium. Eur. J. Immunol. 1975.5: 245-251Cell-mediated lysis of virus-infected cells 247Five times 1 O6 infected o r noninfected mastocytoma cells were suspended in 0.2 ml medium and 100 yCi "Cr (sodiumchromat, Amersham, Buchler, Braunschweig N o CJSlP. spec. activity 100-200 mCi/mg Cr) was added. After 2 h incubation the cells were washed three times, resuspended to the required concent...

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Effects of Adenine Arabinoside on Cellular Immune Mechanisms in Humans

Cited by 52 publications

References 9 publications

Effect of anti-herpesvirus drugs on human and bovine lymphoid function in vitro

Effect of anti-herpesvirus drugs on human and bovine lymphoid function in vitro

Effects of Interferon and Adenine Arabinoside Treatment of Hepatitis B Virus Infection on Cellular Immune Responses

Target cell‐dependent T cell‐mediated lysis of vaccinia virus‐infected cells

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