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Functional and in Situ Evidence for Nitric Oxide Production Driven by CD40-CD40L Interactions in Graft-versus-Leukemia Reactivity¹

Division of Cellular Immunology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany [S. M., V. U., V. S.]; Glaxo Wellcome, Stevenage, Hertfordshire, United Kingdom [M. R.]; and Department of Immunology, Erasmus University Rotterdam, 3000 DR Rotterdam, the Netherlands [J. D. L.]

In a murine tumor model, complete tumor remission is achievable at even advanced metastasized stages by transfer of immune T cells from donor B10.D2 (H-2^d, Mls^b) into tumor-bearing DBA/2 (H-2^d, Mls^a) mice. We showed previously that this graft-versus-leukemia (GvL) effect is dependent on synergistic interactions of transferred CD4+ and CD8+ T cells with host sialoadhesin (SER)-positive macrophages. We now show that the CD40-CD40L (CD154) interaction is involved in the induction of inducible nitric oxide synthase (iNOS) expression during adoptive immunotherapy (ADI). We demonstrate that during ADI, the level of CD40 expression in the liver becomes significantly augmented in comparison to livers of tumor-bearing, untreated animals. CD40 expression is found mostly on SER+ macrophages and to a lesser extent on dendritic cells (DCs). In GvL animals, more SER+ macrophages express iNOS than untreated animals. iNOS expressing cells are found in close proximity to apoptotic cells, at early time points of the therapy in areas of metastasis, and at late stages around portal veins, where CD4+ and CD8+ T lymphocytes form clusters with SER+ macrophages. Blocking of CD40L in vivo at days 5 and 20, when all iNOS+ cells express CD40, leads to significantly reduced CD40 and iNOS expression as well as to a marked inhibition of the therapeutic effect. These data provide functional and in situ evidence that the increased CD40 and iNOS expression observed during ADI contribute to the eradication of liver metastases and to the clearance of donor lymphocytes from the liver.

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