Skip to main content
NCBI home page
Immunology logoLink to Immunology
. 1991 Apr;72(4):571–576.

Penicillamine and penicillin can generate antigenic determinants on rat peritoneal cells in vitro.

C A O'Donnell 1, A L Foster 1, J W Coleman 1
PMCID: PMC1384379  PMID: 1709917

Abstract

Conjugation of the protein-reactive drugs D-penicillamine (PA) and benzylpenicillin (BP) to immune cells to generate drug-derived antigenic determinants has been implicated in drug-induced allergies and autoimmunity. We have therefore developed an in vitro system to demonstrate and characterize the formation of cellular antigens by these drugs. Binding of PA and BP to rat peritoneal exudate cells was detected by a cell ELISA, employing rabbit antisera specific for each drug, and an indicator system employing a second antibody coupled to biotin-streptavidin-beta-galactosidase. For both drugs, binding was detected over the concentration range 125-1000 micrograms/ml. PA bound cells rapidly (maximum binding within 10 min), whereas BP bound relatively slowly (maximum binding occurring later than 4 hr). A possible role for intracellular processing and cellular metabolic activity in the generation of these drug-derived antigenic determinants was examined. Pretreatment of the cells with the fixative paraformaldehyde significantly enhanced binding of PA but not BP. Treatment of cells with the lysosomotropic agents ammonium chloride or chloroquine, or with the metabolic inactivator sodium azide, did not affect the binding of either drug compared with untreated control cells. However, treatment with the oxidising agent copper sulphate, or the cellular activator phorbol myristate acetate, did significantly enhance binding of both drugs to the cells. Therefore, binding of PA and BP to the cell surface appears not to require an intracellular processing event to generate a recognizable antigenic determinant, but is enhanced by treatments that stimulate oxidative processes.

Full text

PDF
571

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahlstedt S., Kristofferson A. Immune mechanisms for induction of penicillin allergy. Prog Allergy. 1982;30:67–134. [PubMed] [Google Scholar]
  2. Bayer E. A., Skutelsky E., Wilchek M. The avidin-biotin complex in affinity cytochemistry. Methods Enzymol. 1979;62:308–315. doi: 10.1016/0076-6879(79)62235-8. [DOI] [PubMed] [Google Scholar]
  3. Bell S. J., Pichler W. J. Penicillin-allergic patients react to penicillin-modified "self". Allergy. 1989 Apr;44(3):199–203. doi: 10.1111/j.1398-9995.1989.tb02262.x. [DOI] [PubMed] [Google Scholar]
  4. Binderup L., Arrigoni-Martelli E. [14C]-D-Penicillamine: uptake and distribution in rat lymphocytes and macrophages. Biochem Pharmacol. 1979;28(2):189–192. doi: 10.1016/0006-2952(79)90501-x. [DOI] [PubMed] [Google Scholar]
  5. Chain B. M., Kaye P. M., Shaw M. A. The biochemistry and cell biology of antigen processing. Immunol Rev. 1988 Dec;106:33–58. doi: 10.1111/j.1600-065x.1988.tb00772.x. [DOI] [PubMed] [Google Scholar]
  6. Claas F. H., van Rood J. J. The interaction of drugs and endogeneous substances with HLA class-I antigens. Prog Allergy. 1985;36:135–150. [PubMed] [Google Scholar]
  7. Coleman J. W., Foster A. L., Yeung J. H., Park B. K. Drug-protein conjugates--XV. A study of the disposition of D-penicillamine in the rat and its relationship to immunogenicity. Biochem Pharmacol. 1988 Feb 15;37(4):737–742. doi: 10.1016/0006-2952(88)90148-7. [DOI] [PubMed] [Google Scholar]
  8. Foster A. L., Park B. K., Coleman J. W. A specific enzyme-linked immunosorbent assay for definition of the IgG antibody response to disulphide-conjugated D-penicillamine in the rabbit. Int Arch Allergy Appl Immunol. 1987;84(3):271–276. doi: 10.1159/000234434. [DOI] [PubMed] [Google Scholar]
  9. Gao X. M., Rhodes J. An essential role for constitutive Schiff base-forming ligands in antigen presentation to murine T cell clones. J Immunol. 1990 Apr 15;144(8):2883–2890. [PubMed] [Google Scholar]
  10. Hill H. F. Penicillamine in rheumatoid arthritis: adverse effects. Scand J Rheumatol Suppl. 1979;(28):94–99. doi: 10.3109/03009747909108247. [DOI] [PubMed] [Google Scholar]
  11. Kitteringham N. R., Christie G., Coleman J. W., Yeung J. H., Park B. K. Drug-protein conjugates--XII. A study of the disposition, irreversible binding and immunogenicity of penicillin in the rat. Biochem Pharmacol. 1987 Mar 1;36(5):601–608. doi: 10.1016/0006-2952(87)90708-8. [DOI] [PubMed] [Google Scholar]
  12. Lengfelder E., Fuchs C., Younes M., Weser U. Functional aspects of the superoxide dismutative action of Cu-penicillamine. Biochim Biophys Acta. 1979 Apr 12;567(2):492–502. doi: 10.1016/0005-2744(79)90135-9. [DOI] [PubMed] [Google Scholar]
  13. Nagata N., Hurtenbach U., Gleichmann E. Specific sensitization of Lyt-1+2- T cells to spleen cells modified by the drug D-penicillamine or a stereoisomer. J Immunol. 1986 Jan;136(1):136–142. [PubMed] [Google Scholar]
  14. Park B. K., Coleman J. W., Kitteringham N. R. Drug disposition and drug hypersensitivity. Biochem Pharmacol. 1987 Mar 1;36(5):581–590. [PubMed] [Google Scholar]
  15. Streicher H. Z., Berkower I. J., Busch M., Gurd F. R., Berzofsky J. A. Antigen conformation determines processing requirements for T-cell activation. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6831–6835. doi: 10.1073/pnas.81.21.6831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Watanabe H., Grimsley G., Major G. A., Dawkins R. L. Increased binding of D-penicillamine to monocytes in rheumatoid arthritis. Clin Immunol Immunopathol. 1986 Apr;39(1):173–178. doi: 10.1016/0090-1229(86)90217-5. [DOI] [PubMed] [Google Scholar]
  17. Watanabe H., Kelly H., Dawkins R. L. Association of HLA DR1 with high D-penicillamine binding to monocytes in females. Microbiol Immunol. 1987;31(1):83–88. doi: 10.1111/j.1348-0421.1987.tb03070.x. [DOI] [PubMed] [Google Scholar]
  18. Ziegler H. K., Unanue E. R. Decrease in macrophage antigen catabolism caused by ammonia and chloroquine is associated with inhibition of antigen presentation to T cells. Proc Natl Acad Sci U S A. 1982 Jan;79(1):175–178. doi: 10.1073/pnas.79.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ziegler K., Unanue E. R. Identification of a macrophage antigen-processing event required for I-region-restricted antigen presentation to T lymphocytes. J Immunol. 1981 Nov;127(5):1869–1875. [PubMed] [Google Scholar]
  20. Zucker-Franklin D., Lavie G., Franklin E. C. Demonstration of membrane-bound proteolytic activity on the surface of mononuclear leukocytes. J Histochem Cytochem. 1981 Mar;29(3A):451–456. doi: 10.1177/29.3.451. [DOI] [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES