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J Exp Med. Feb 1, 1994; 179(2): 493–502.
PMCID: PMC2191349

High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells

Abstract

Transplantation of HLA mismatched hematopoietic stem cells in patients with severe combined immunodeficiency (SCID) can result in a selective engraftment of T cells of donor origin with complete immunologic reconstitution and in vivo tolerance. The latter may occur in the absence of clonal deletion of donor T lymphocytes able to recognize the host HLA antigens. The activity of these host-reactive T cells is suppressed in vivo, since no graft-vs. -host disease is observed in these human chimeras. Here it is shown that the CD4+ host-reactive T cell clones isolated from a SCID patient transplanted with fetal liver stem cells produce unusually high quantities of interleukin 10 (IL-10) and very low amounts of IL-2 after antigen-specific stimulation in vitro. The specific proliferative responses of the host-reactive T cell clones were considerably enhanced in the presence of neutralizing concentrations of an anti-IL-10 monoclonal antibody, suggesting that high levels of endogenous IL-10 suppress the activity of these cells. These in vitro data correlate with observations made in vivo. Semi- quantitative polymerase chain reaction analysis carried out on freshly isolated peripheral blood mononuclear cells (PBMC) of the patient indicated that the levels of IL-10 messenger RNA (mRNA) expression were strongly enhanced, whereas IL-2 mRNA expression was much lower than that in PBMC of healthy donors. In vivo IL-10 mRNA expression was not only high in the T cells, but also in the non-T cell fraction, indicating that host cells also contributed to the high levels of IL-10 in vivo. Patient-derived monocytes were found to be major IL-10 producers. Although no circulating IL-10 could be detected, freshly isolated monocytes of the patient showed a reduced expression of class II HLA antigens. However, their capacity to stimulate T cells of normal donors in primary mixed lymphocyte cultures was within the normal range. Interestingly, similar high in vivo IL-10 mRNA expressions in the T and non-T cell compartment were also observed in three SCID patients transplanted with fetal liver stem cells and in four SCID patients transplanted with T cell-depleted haploidentical bone marrow stem cells. Taken together, these data indicate that high endogenous IL- 10 production is a general phenomenon in SCID patients in whom allogenic stem cell transplantation results in immunologic reconstitution and induction of tolerance. Both donor T cells and host accessory cells contribute to these high levels of IL-10, which would suppress the activity of host-reactive T cell in vivo.

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Selected References

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  • Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood. 1992 Dec 15;80(12):2964–2968. [PubMed]
  • Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med. 1991 Mar 7;324(10):667–674. [PubMed]
  • Parkman R. Human graft-versus-host disease. Immunodefic Rev. 1991;2(4):253–264. [PubMed]
  • Fischer A, Landais P, Friedrich W, Morgan G, Gerritsen B, Fasth A, Porta F, Griscelli C, Goldman SF, Levinsky R, et al. European experience of bone-marrow transplantation for severe combined immunodeficiency. Lancet. 1990 Oct 6;336(8719):850–854. [PubMed]
  • Parkman R. The biology of bone marrow transplantation for severe combined immune deficiency. Adv Immunol. 1991;49:381–410. [PubMed]
  • O'Reilly RJ, Keever CA, Small TN, Brochstein J. The use of HLA-non-identical T-cell-depleted marrow transplants for correction of severe combined immunodeficiency disease. Immunodefic Rev. 1989;1(4):273–309. [PubMed]
  • Roncarolo MG, Touraine JL, Banchereau J. Cooperation between major histocompatibility complex mismatched mononuclear cells from a human chimera in the production of antigen-specific antibody. J Clin Invest. 1986 Mar;77(3):673–680. [PMC free article] [PubMed]
  • Roncarolo MG, Yssel H, Touraine JL, Bacchetta R, Gebuhrer L, De Vries JE, Spits H. Antigen recognition by MHC-incompatible cells of a human mismatched chimera. J Exp Med. 1988 Dec 1;168(6):2139–2152. [PMC free article] [PubMed]
  • Roncarolo MG, Yssel H, Touraine JL, Betuel H, De Vries JE, Spits H. Autoreactive T cell clones specific for class I and class II HLA antigens isolated from a human chimera. J Exp Med. 1988 May 1;167(5):1523–1534. [PMC free article] [PubMed]
  • Bacchetta R, Vandekerckhove BA, Touraine JL, Bigler M, Martino S, Gebuhrer L, de Vries JE, Spits H, Roncarolo MG. Chimerism and tolerance to host and donor in severe combined immunodeficiencies transplanted with fetal liver stem cells. J Clin Invest. 1993 Mar;91(3):1067–1078. [PMC free article] [PubMed]
  • Ramsdell F, Fowlkes BJ. Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance. Science. 1990 Jun 15;248(4961):1342–1348. [PubMed]
  • Jenkins MK, Schwartz RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302–319. [PMC free article] [PubMed]
  • Howard M, O'Garra A, Ishida H, de Waal Malefyt R, de Vries J. Biological properties of interleukin 10. J Clin Immunol. 1992 Jul;12(4):239–247. [PubMed]
  • de Waal Malefyt R, Yssel H, Roncarolo MG, Spits H, de Vries JE. Interleukin-10. Curr Opin Immunol. 1992 Jun;4(3):314–320. [PubMed]
  • de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. [PMC free article] [PubMed]
  • Yssel H, De Waal Malefyt R, Roncarolo MG, Abrams JS, Lahesmaa R, Spits H, de Vries JE. IL-10 is produced by subsets of human CD4+ T cell clones and peripheral blood T cells. J Immunol. 1992 Oct 1;149(7):2378–2384. [PubMed]
  • de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, Figdor C, Johnson K, Kastelein R, Yssel H, de Vries JE. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. [PMC free article] [PubMed]
  • de Waal Malefyt R, Yssel H, de Vries JE. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol. 1993 Jun 1;150(11):4754–4765. [PubMed]
  • Bejarano MT, de Waal Malefyt R, Abrams JS, Bigler M, Bacchetta R, de Vries JE, Roncarolo MG. Interleukin 10 inhibits allogeneic proliferative and cytotoxic T cell responses generated in primary mixed lymphocyte cultures. Int Immunol. 1992 Dec;4(12):1389–1397. [PubMed]
  • Touraine JL, Bétuel H. Immunodeficiency diseases and expression of HLA antigens. Hum Immunol. 1981 Mar;2(2):147–153. [PubMed]
  • Touraine JL, Raudrant D, Royo C, Rebaud A, Roncarolo MG, Souillet G, Philippe N, Touraine F, Bétuel H. In-utero transplantation of stem cells in bare lymphocyte syndrome. Lancet. 1989 Jun 17;1(8651):1382–1382. [PubMed]
  • Hervé P, Wijdenes J, Bergerat JP, Bordigoni P, Milpied N, Cahn JY, Clément C, Béliard R, Morel-Fourrier B, Racadot E, et al. Treatment of corticosteroid resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10) Blood. 1990 Feb 15;75(4):1017–1023. [PubMed]
  • Spits H, Keizer G, Borst J, Terhorst C, Hekman A, de Vries JE. Characterization of monoclonal antibodies against cell surface molecules associated with cytotoxic activity of natural and activated killer cells and cloned CTL lines. Hybridoma. 1983;2(4):423–437. [PubMed]
  • Vieira P, de Waal-Malefyt R, Dang MN, Johnson KE, Kastelein R, Fiorentino DF, deVries JE, Roncarolo MG, Mosmann TR, Moore KW. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. [PMC free article] [PubMed]
  • O'Garra A, Vieira P. Polymerase chain reaction for detection of cytokine gene expression. Curr Opin Immunol. 1992 Apr;4(2):211–215. [PubMed]
  • Murphy E, Hieny S, Sher A, O'Garra A. Detection of in vivo expression of interleukin-10 using a semi-quantitative polymerase chain reaction method in Schistosoma mansoni infected mice. J Immunol Methods. 1993 Jun 18;162(2):211–223. [PubMed]
  • Keever CA, Flomenberg N, Brochstein J, Sullivan M, Collins NH, Burns J, Dupont B, O'Reilly RJ. Tolerance of engrafted donor T cells following bone marrow transplantation for severe combined immunodeficiency. Clin Immunol Immunopathol. 1988 Sep;48(3):261–276. [PubMed]
  • Schiff SE, Buckley RH. Modified responses to recipient and donor B cells by genetically donor T cells from human haploidentical bone marrow chimeras. J Immunol. 1987 Apr 1;138(7):2088–2094. [PubMed]
  • McCarthy PL, Jr, Abhyankar S, Neben S, Newman G, Sieff C, Thompson RC, Burakoff SJ, Ferrara JL. Inhibition of interleukin-1 by an interleukin-1 receptor antagonist prevents graft-versus-host disease. Blood. 1991 Oct 15;78(8):1915–1918. [PubMed]
  • Piguet PF, Grau GE, Allet B, Vassalli P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J Exp Med. 1987 Nov 1;166(5):1280–1289. [PMC free article] [PubMed]
  • Symington FW, Pepe MS, Chen AB, Deliganis A. Serum tumor necrosis factor alpha associated with acute graft-versus-host disease in humans. Transplantation. 1990 Sep;50(3):518–521. [PubMed]
  • Niederwieser D, Herold M, Woloszczuk W, Aulitzky W, Meister B, Tilg H, Gastl G, Bowden R, Huber C. Endogenous IFN-gamma during human bone marrow transplantation. Analysis of serum levels of interferon and interferon-dependent secondary messages. Transplantation. 1990 Oct;50(4):620–625. [PubMed]
  • Hervé P, Flesch M, Tiberghien P, Wijdenes J, Racadot E, Bordigoni P, Plouvier E, Stephan JL, Bourdeau H, Holler E, et al. Phase I-II trial of a monoclonal anti-tumor necrosis factor alpha antibody for the treatment of refractory severe acute graft-versus-host disease. Blood. 1992 Jun 15;79(12):3362–3368. [PubMed]
  • Essery G, Feldmann M, Lamb JR. Interleukin-2 can prevent and reverse antigen-induced unresponsiveness in cloned human T lymphocytes. Immunology. 1988 Jul;64(3):413–417. [PMC free article] [PubMed]
  • Vandekerckhove BA, Namikawa R, Bacchetta R, Roncarolo MG. Human hematopoietic cells and thymic epithelial cells induce tolerance via different mechanisms in the SCID-hu mouse thymus. J Exp Med. 1992 Apr 1;175(4):1033–1043. [PMC free article] [PubMed]

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