Alteration in spleen lymphoid populations associated with specific amino acid depletion during l-asparaginase treatment

John A. Distasio, Donald L. Durden, Ronald D. Paul, Mehrdad Nadji

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13 Scopus citations

Abstract

Treatment with antileukemic asparaginases isolated from Escherichia coli and Erwinia carotovora is accompanied by pronounced toxicity and immunosuppression. The capability of these enzymes to hydrolyze L-glutamine and to limit serum levels of this amino acid as well as asparagine has led investigators to hypothesize that glutaminase activity may be responsible for the side effects observed during treatment. We have isolated a glutaminase-free asparaginase with potent antilymphoma activity from Vibrio succinogenes. With the use of this enzyme, we have demonstrated that asparagine depletion alone does not result in suppression of humoral or cell-mediated responses after immunization with sheep red blood cells. In contrast, treatment with E. coli asparaginase abolishes these immune responses. In the present study, we investigated the effects of specific amino acid depletion resulting from asparaginase treatment on spleen histology and lymphocyte populations. Administration by i.p. injection of 50 IU of E. coli asparaginase per day for 4 days resulted in a marked reduction in the size of lymphoid follicles within the spleen concomitant with reduced germinal centers. There appeared to be a significant change in reactivity of the germinal centers, evidenced by a decrease in immunoblasts (B-cells). These findings were confirmed by a sensitive peroxidase-antiperoxidase staining procedure for immunoglobulin-containing cells. Examination of lymphocyte subpopulations within the spleen revealed that there was nearly a 40% decrease in the percentage of Slg-bearing cells accompanied by an increase in the ratio of Thy 1.2-bearing cells. The ratio of Lyt-2 to Lyt-1 cells was unchanged as compared to control animals. The data support the hypothesis that glutamine or glutamine combined with asparagine depletion resulting from the treatment of E. coli asparaginase causes a marked decrease in spleen lymphocytes of the B-cell lineage. In contrast, asparagine deprivation alone, caused by the administration of the glutaminase-free asparaginase from V. succinogenes, does not affect spleen histology or lymphocyte marker distribution. Thus, the asparaginase from V. succinogenes should serve as an effective antileukemic agent without causing deleterious effects on the immune system.

Original languageEnglish (US)
Pages (from-to)252-258
Number of pages7
JournalCancer Research
Volume42
Issue number1
Publication statusPublished - Jan 1 1982

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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