Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Dec 15;98(12):2819–2826. doi: 10.1172/JCI119110

Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells.

M G Wing 1, T Moreau 1, J Greenwood 1, R M Smith 1, G Hale 1, J Isaacs 1, H Waldmann 1, P J Lachmann 1, A Compston 1
PMCID: PMC507749  PMID: 8981930

Abstract

The administration of the immunosuppressive humanized monoclonal antibody CAMPATH 1-H, which recognizes CD52 on lymphocytes and monocytes, is associated with a first-dose cytokine-release syndrome involving TNFalpha, IFNgamma, and IL-6 clinically. In vitro models have been used to establish the cellular source and mechanism responsible for cytokine release, demonstrating that cytokine release is isotype dependent, with the rat IgG2b and human IgG1 isotype inducing the highest levels of cytokine release, which was inhibited with antibody to CD16, the low affinity Fc-receptor for IgG (FcgammaR). Cross-linking antibody opsonized CD4 T lymphocytes failed to stimulate TNFalpha release, which together with the observation that TNFalpha release by purified natural killer (NK) cells stimulated by fixed autologous CAMPATH 1-H-opsonized targets was inhibited with anti-CD16, indicates that cytokine release results from ligation of CD16 on the NK cells, rather than Fc-receptor (FcR)-dependent cross-linking of CD52 on the targeted cell. Since the hierarchy of isotypes inducing cytokine release in these cultures matches that seen clinically, we conclude that ligation of CD16 on NK cells is also responsible for cytokine release after injection of CAMPATH 1-H in vivo.

Full Text

The Full Text of this article is available as a PDF (197.8 KB).

Selected References

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

  1. Alegre M. L., Collins A. M., Pulito V. L., Brosius R. A., Olson W. C., Zivin R. A., Knowles R., Thistlethwaite J. R., Jolliffe L. K., Bluestone J. A. Effect of a single amino acid mutation on the activating and immunosuppressive properties of a "humanized" OKT3 monoclonal antibody. J Immunol. 1992 Jun 1;148(11):3461–3468. [PubMed] [Google Scholar]
  2. Alegre M. L., Peterson L. J., Xu D., Sattar H. A., Jeyarajah D. R., Kowalkowski K., Thistlethwaite J. R., Zivin R. A., Jolliffe L., Bluestone J. A. A non-activating "humanized" anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation. 1994 Jun 15;57(11):1537–1543. [PubMed] [Google Scholar]
  3. Anegón I., Cuturi M. C., Trinchieri G., Perussia B. Interaction of Fc receptor (CD16) ligands induces transcription of interleukin 2 receptor (CD25) and lymphokine genes and expression of their products in human natural killer cells. J Exp Med. 1988 Feb 1;167(2):452–472. doi: 10.1084/jem.167.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arya S. K., Wong-Staal F., Gallo R. C. Dexamethasone-mediated inhibition of human T cell growth factor and gamma-interferon messenger RNA. J Immunol. 1984 Jul;133(1):273–276. [PubMed] [Google Scholar]
  5. Bauer J., Ganter U., Geiger T., Jacobshagen U., Hirano T., Matsuda T., Kishimoto T., Andus T., Acs G., Gerok W. Regulation of interleukin-6 expression in cultured human blood monocytes and monocyte-derived macrophages. Blood. 1988 Oct;72(4):1134–1140. [PubMed] [Google Scholar]
  6. Bazzoni F., Cassatella M. A., Laudanna C., Rossi F. Phagocytosis of opsonized yeast induces tumor necrosis factor-alpha mRNA accumulation and protein release by human polymorphonuclear leukocytes. J Leukoc Biol. 1991 Sep;50(3):223–228. doi: 10.1002/jlb.50.3.223. [DOI] [PubMed] [Google Scholar]
  7. Butler T., Möller G. Mitogenic response of mouse spleen cells and gelation of limulus lysate by lipopolysaccharide of Yersinia pestis and evidence for neutralization of lipopolysaccharide by polymyxin B. Infect Immun. 1977 Nov;18(2):400–404. doi: 10.1128/iai.18.2.400-404.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chatenoud L., Ferran C., Legendre C., Thouard I., Merite S., Reuter A., Gevaert Y., Kreis H., Franchimont P., Bach J. F. In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids. Transplantation. 1990 Apr;49(4):697–702. doi: 10.1097/00007890-199004000-00009. [DOI] [PubMed] [Google Scholar]
  9. Cosimi A. B., Burton R. C., Colvin R. B., Goldstein G., Delmonico F. L., LaQuaglia M. P., Tolkoff-Rubin N., Rubin R. H., Herrin J. T., Russell P. S. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation. 1981 Dec;32(6):535–539. doi: 10.1097/00007890-198112000-00018. [DOI] [PubMed] [Google Scholar]
  10. Dyer M. J., Hale G., Hayhoe F. G., Waldmann H. Effects of CAMPATH-1 antibodies in vivo in patients with lymphoid malignancies: influence of antibody isotype. Blood. 1989 May 1;73(6):1431–1439. [PubMed] [Google Scholar]
  11. Fraser J. D., Straus D., Weiss A. Signal transduction events leading to T-cell lymphokine gene expression. Immunol Today. 1993 Jul;14(7):357–362. doi: 10.1016/0167-5699(93)90236-E. [DOI] [PubMed] [Google Scholar]
  12. Friend P. J., Rebello P., Oliveira D., Manna V., Cobbold S. P., Hale G., Jamieson N. V., Jamieson I., Calne R. Y., Harris D. T. Successful treatment of renal allograft rejection with a humanized antilymphocyte monoclonal antibody. Transplant Proc. 1995 Feb;27(1):869–870. [PubMed] [Google Scholar]
  13. Greenwood J., Clark M., Waldmann H. Structural motifs involved in human IgG antibody effector functions. Eur J Immunol. 1993 May;23(5):1098–1104. doi: 10.1002/eji.1830230518. [DOI] [PubMed] [Google Scholar]
  14. Hale G., Dyer M. J., Clark M. R., Phillips J. M., Marcus R., Riechmann L., Winter G., Waldmann H. Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody CAMPATH-1H. Lancet. 1988 Dec 17;2(8625):1394–1399. doi: 10.1016/s0140-6736(88)90588-0. [DOI] [PubMed] [Google Scholar]
  15. Hale G., Xia M. Q., Tighe H. P., Dyer M. J., Waldmann H. The CAMPATH-1 antigen (CDw52). Tissue Antigens. 1990 Mar;35(3):118–127. doi: 10.1111/j.1399-0039.1990.tb01767.x. [DOI] [PubMed] [Google Scholar]
  16. Han J., Thompson P., Beutler B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med. 1990 Jul 1;172(1):391–394. doi: 10.1084/jem.172.1.391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hirsch R., Bluestone J. A., Bare C. V., Gress R. E. Advantages of F(ab')2 fragments of anti-CD3 monoclonal antibody as compared to whole antibody as immunosuppressive agents in mice. Transplant Proc. 1991 Feb;23(1 Pt 1):270–271. [PubMed] [Google Scholar]
  18. Isaacs J. D., Watts R. A., Hazleman B. L., Hale G., Keogan M. T., Cobbold S. P., Waldmann H. Humanised monoclonal antibody therapy for rheumatoid arthritis. Lancet. 1992 Sep 26;340(8822):748–752. doi: 10.1016/0140-6736(92)92294-p. [DOI] [PubMed] [Google Scholar]
  19. Jefferis R., Lund J., Pound J. Molecular definition of interaction sites on human IgG for Fc receptors (huFc gamma R). Mol Immunol. 1990 Dec;27(12):1237–1240. doi: 10.1016/0161-5890(90)90027-w. [DOI] [PubMed] [Google Scholar]
  20. Lanier L. L., Yu G., Phillips J. H. Co-association of CD3 zeta with a receptor (CD16) for IgG Fc on human natural killer cells. Nature. 1989 Dec 14;342(6251):803–805. doi: 10.1038/342803a0. [DOI] [PubMed] [Google Scholar]
  21. Letourneur O., Kennedy I. C., Brini A. T., Ortaldo J. R., O'Shea J. J., Kinet J. P. Characterization of the family of dimers associated with Fc receptors (Fc epsilon RI and Fc gamma RIII). J Immunol. 1991 Oct 15;147(8):2652–2656. [PubMed] [Google Scholar]
  22. Lockwood C. M., Thiru S., Isaacs J. D., Hale G., Waldmann H. Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet. 1993 Jun 26;341(8861):1620–1622. doi: 10.1016/0140-6736(93)90759-a. [DOI] [PubMed] [Google Scholar]
  23. Mathieson P. W., Cobbold S. P., Hale G., Clark M. R., Oliveira D. B., Lockwood C. M., Waldmann H. Monoclonal-antibody therapy in systemic vasculitis. N Engl J Med. 1990 Jul 26;323(4):250–254. doi: 10.1056/NEJM199007263230407. [DOI] [PubMed] [Google Scholar]
  24. Melero I., Balboa M. A., Alonso J. L., Yagüe E., Pivel J. P., Sanchez-Madrid F., López-Botet M. Signaling through the LFA-1 leucocyte integrin actively regulates intercellular adhesion and tumor necrosis factor-alpha production in natural killer cells. Eur J Immunol. 1993 Aug;23(8):1859–1865. doi: 10.1002/eji.1830230819. [DOI] [PubMed] [Google Scholar]
  25. Moreau T., Coles A., Wing M., Isaacs J., Hale G., Waldmann H., Compston A. Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain. 1996 Feb;119(Pt 1):225–237. doi: 10.1093/brain/119.1.225. [DOI] [PubMed] [Google Scholar]
  26. Moreau T., Thorpe J., Miller D., Moseley I., Hale G., Waldmann H., Clayton D., Wing M., Scolding N., Compston A. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet. 1994 Jul 30;344(8918):298–301. doi: 10.1016/s0140-6736(94)91339-0. [DOI] [PubMed] [Google Scholar]
  27. Morrison D. C., Curry B. J. The use of polymyxin B and C3H/HeJ mouse spleen cells as criteria for endotoxin contamination. J Immunol Methods. 1979 May 10;27(1):83–92. doi: 10.1016/0022-1759(79)90241-2. [DOI] [PubMed] [Google Scholar]
  28. Navarro S., Debili N., Bernaudin J. F., Vainchenker W., Doly J. Regulation of the expression of IL-6 in human monocytes. J Immunol. 1989 Jun 15;142(12):4339–4345. [PubMed] [Google Scholar]
  29. Nishimura T., Itoh T. Higher level expression of lymphocyte function-associated antigen-1 (LFA-1) on in vivo natural killer cells. Eur J Immunol. 1988 Dec;18(12):2077–2080. doi: 10.1002/eji.1830181231. [DOI] [PubMed] [Google Scholar]
  30. Okusawa S., Yancey K. B., van der Meer J. W., Endres S., Lonnemann G., Hefter K., Frank M. M., Burke J. F., Dinarello C. A., Gelfand J. A. C5a stimulates secretion of tumor necrosis factor from human mononuclear cells in vitro. Comparison with secretion of interleukin 1 beta and interleukin 1 alpha. J Exp Med. 1988 Jul 1;168(1):443–448. doi: 10.1084/jem.168.1.443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Parlevliet K. J., ten Berge I. J., Yong S. L., Surachno J., Wilmink J. M., Schellekens P. T. In vivo effects of IgA and IgG2a anti-CD3 isotype switch variants. J Clin Invest. 1994 Jun;93(6):2519–2525. doi: 10.1172/JCI117262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Perussia B., Starr S., Abraham S., Fanning V., Trinchieri G. Human natural killer cells analyzed by B73.1, a monoclonal antibody blocking Fc receptor functions. I. Characterization of the lymphocyte subset reactive with B73.1. J Immunol. 1983 May;130(5):2133–2141. [PubMed] [Google Scholar]
  33. Riechmann L., Clark M., Waldmann H., Winter G. Reshaping human antibodies for therapy. Nature. 1988 Mar 24;332(6162):323–327. doi: 10.1038/332323a0. [DOI] [PubMed] [Google Scholar]
  34. Robertson M. J., Caligiuri M. A., Manley T. J., Levine H., Ritz J. Human natural killer cell adhesion molecules. Differential expression after activation and participation in cytolysis. J Immunol. 1990 Nov 15;145(10):3194–3201. [PubMed] [Google Scholar]
  35. Rowan W. C., Hale G., Tite J. P., Brett S. J. Cross-linking of the CAMPATH-1 antigen (CD52) triggers activation of normal human T lymphocytes. Int Immunol. 1995 Jan;7(1):69–77. doi: 10.1093/intimm/7.1.69. [DOI] [PubMed] [Google Scholar]
  36. Sarmay G., Lund J., Rozsnyay Z., Gergely J., Jefferis R. Mapping and comparison of the interaction sites on the Fc region of IgG responsible for triggering antibody dependent cellular cytotoxicity (ADCC) through different types of human Fc gamma receptor. Mol Immunol. 1992 May;29(5):633–639. doi: 10.1016/0161-5890(92)90200-h. [DOI] [PubMed] [Google Scholar]
  37. Shalaby M. R., Waage A., Espevik T. Cytokine regulation of interleukin 6 production by human endothelial cells. Cell Immunol. 1989 Jul;121(2):372–382. doi: 10.1016/0008-8749(89)90036-1. [DOI] [PubMed] [Google Scholar]
  38. Stein M., Gordon S. Regulation of tumor necrosis factor (TNF) release by murine peritoneal macrophages: role of cell stimulation and specific phagocytic plasma membrane receptors. Eur J Immunol. 1991 Feb;21(2):431–437. doi: 10.1002/eji.1830210227. [DOI] [PubMed] [Google Scholar]
  39. Waage A., Slupphaug G., Shalaby R. Glucocorticoids inhibit the production of IL6 from monocytes, endothelial cells and fibroblasts. Eur J Immunol. 1990 Nov;20(11):2439–2443. doi: 10.1002/eji.1830201112. [DOI] [PubMed] [Google Scholar]
  40. Wing M. G., Montgomery A. M., Harley C., Lachmann P. J. Cytostasis of different tumours by a murine PPD-reactive CD4+ T lymphocyte clone is mediated by interferon-gamma and tumour necrosis factor alone or synergistically. Clin Exp Immunol. 1990 Nov;82(2):208–213. doi: 10.1111/j.1365-2249.1990.tb05428.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES