Augmentation by transferrin of IL-2-inducible killer activity and perform production of human CD8+ T cells

Transferrin receptor (TfR) expression is up-regulated during T cell activation after the interaction of the T cell receptor with the antigenmajor histocompatibility complex and the expression of interleukin-2 (IL-2) receptor. We hypothesize that anti-TfR monoclonal antibody (mAb) will prolong allograft survival by altering T cell responses. In a murine heterotopic nonvascularized cardiac allograft model, CBA/J (H-2 k ) recipients were transplanted with neonatal C57BL/6 (H-2 b ) donor hearts. Anti-TfR or isotype-matched control mAbs (100 g) were administered at the time of transplantation and on the following day. Splenocytes from naive CBA/J mice were stimulated in vitro with C57BL/6 alloantigen. Anti-TfR mAb was administered at 5 g/mL during the initiation of culture. Cytotoxic T lymphocyte (CTL) and mixed lymphocyte responses (MLR) were performed to assess T cell function. After 24 h in culture, cells were harvested, RNA isolated, and semi-quantitative reverse transcriptase-polymerase chain reaction performed. Anti-TfR mAb prolonged allograft survival to 25.7 ؎ 0.9 days compared to the isotype control (10.7 ؎ 0.4 days, P F 0.01, Wilcoxon rank sum). Anti-TfR mAb completely abrogated the CTL response and suppressed the MLR by 70-86% compared to the isotype controls. Anti-TfR mAb suppressed IL-2, interferon-␥ (IFN-␥), IL-10, and IL-12 p40 mRNA expression, but had no effect on IL-4, IL-12 p35, and IL-15 mRNA expression. In conclusion, anti-TfR mAb prolongs allograft survival, suppresses T cell function, and alters IL-2, IL-10, IL-12 p40, and IFN-␥ mRNA expression. These data suggest that the downregulation in IL-12 mRNA by anti-TfR mAb may prevent the development of T helper cells, thereby promoting graft survival and altering cell-mediated immune responses. The partial effect by anti-TfR mAb on cytokine mRNA expression may be due to other contributing factors such as costimulation.

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Transferrin receptor in T cell activation and transplantation

Bayer

Baliga

Woodward

1998

Journal of Leukocyte Biology

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CD8+ T cell activation correlates with disease activity in clinically isolated syndromes and is regulated by interferon-β treatment

Jensen

Langkilde

Frederiksen

et al. 2006

Journal of Neuroimmunology

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Upregulation of Interleukin-10 and Inhibition of Alloantigen Responses by Transferrin and Transferrin-Derived Glycans

Lesnikova

Lesnikov

Arrighi

et al. 2000

Journal of Hematotherapy & Stem Cell Research

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Previous studies have shown that critically timed administration of transferrin (Tf) facilitates induction of immunologic unresponsiveness. Here, we determined in mixed leukocyte culture (MLC) and in concanavalin A (ConA)-driven cultures the effect of exogenous Tf and Tf-derived glycans (Tf-Gly) on lymphocyte proliferation. In cultures of human blood lymphocytes, Tf inhibited selectively alloantigen-driven proliferation in MLC, but not ConA-stimulated lymphocyte proliferation. Deglycosylation of Tf abrogated the inhibitory effect of Tf on alloantigen-induced lymphocyte proliferation, and, consistent with a role for glycans, an effect qualitatively and quantitatively similar to Tf was exerted by purified Tf-Gly. Glycans isolated from other proteins, for example, immunoglobulin G (IgG) or fibrinogen, failed to inhibit alloantigen-induced proliferation selectively. Rather, they suppressed lymphocyte proliferation in a non-specific manner. Determination of cytokines in MLC supernatant showed a downregulation of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-2, and IL-12 (p40), along with an upregulation of IL-10, a pattern entirely consistent with the observed effects of Tf and Tf-Gly on alloantigen-induced lymphocyte proliferation. The effect of Tf on MLC was directly IL-10-dependent. IL-10 levels were inversely correlated with lymphocyte proliferation and CD86 expression. Neutralization of IL-10 by anti-IL-10 monoclonal antibody (mAb) blocked the effect of Tf. The MLC-modulating effect of Tf (or Tf-Gly) was not dependent upon the Tf receptor CD71 but appeared to be mediated by a Gly-responsive receptor. These data suggest a role of Tf, and, in particular, Tf-Gly, in allo-interactions that is independent from the role of Tf in iron metabolism, and appears to involve co-stimulatory signals.

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Augmentation by transferrin of IL-2-inducible killer activity and perform production of human CD8+ T cells

Cited by 6 publications

References 33 publications

Transferrin receptor in T cell activation and transplantation

Transferrin receptor in T cell activation and transplantation

CD8+ T cell activation correlates with disease activity in clinically isolated syndromes and is regulated by interferon-β treatment

Upregulation of Interleukin-10 and Inhibition of Alloantigen Responses by Transferrin and Transferrin-Derived Glycans

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