Editorial
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World J Transplant. Dec 24, 2013; 3(4): 54-61
Published online Dec 24, 2013. doi: 10.5500/wjt.v3.i4.54
Common and small molecules as the ultimate regulatory and effector mediators of antigen-specific transplantation reactions
Vladimir Holan, Magdalena Krulova
Vladimir Holan, Magdalena Krulova, Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20 Prague 4, Czech Republic
Vladimir Holan, Magdalena Krulova, Faculty of Science, Charles University, 128 44 Prague 2, Czech Republic
Author contributions: All authors contributed equally to this work.
Supported by The Grants P304/11/0653 and P301/11/1568 from the Grant Agency of the Czech Republic; the Grant NT/14102 from the Grant Agency of the Ministry of Health of the Czech Republic; and the projects MSM0021620858 and SVV 265211 from the Ministry of Education of the Czech Republic
Correspondence to: Vladimir Holan, PhD, DSc, Professor of Immunology, Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. holan@biomed.cas.cz
Telephone: +420-241-063226 Fax: +420-224-432699
Received: March 15, 2013
Revised: June 12, 2013
Accepted: August 8, 2013
Published online: December 24, 2013
Processing time: 291 Days and 7 Hours
Abstract

In spite of intensive research, the molecular basis of allograft and xenograft rejection still remains not fully understood. The acute rejection of an allograft is associated with the intragraft Th1 cytokine response, while tolerance of an allograft or xenograft rejection is accompanied by a higher production of the Th2 cytokines interleukin (IL)-4 and IL-10. Nevertheless, these cytokines are not the final regulatory and effector molecules mediating transplantation reactions. Data indicate that the functioning of common molecules with enzymatic activities, such are inducible nitric oxide synthase (iNOS), arginase, heme oxygenase-1 (HO-1) or indoleamine-2,3-dioxygenase (IDO), the bioavailability of their substrates (L-arginine, tryptophan, heme) and the cytotoxic and regulatory actions of their small gaseous products (NO, CO) can be the ultimate mechanisms responsible for effector or regulatory reactions. Using models of transplantation immunity and tolerance we show that T cell receptor-mediated recognition of allogeneic or xenogeneic antigens as well as the balance between immunity/tolerance induces distinct cytokine production profiles. The ratio between Th1 and Th2 cytokines efficiently regulates the expression of genes for common enzymes, such as iNOS, arginase, HO-1 and IDO. These enzymes may compete for substrates, such as L-arginine or tryptophan, and the final product of their activity are small molecules (NO, CO) displaying effector or regulatory functions of the immune system. Thus, it is suggested that in spite of the high immunological specificity of transplatation reaction, the ultimate players in regulatory and effector functions could be small and common molecules.

Keywords: Immunoregulation; Graft rejection; Tolerance; Th1/Th2 balance; Macrophages; Nitric oxide; Arginase

Core tip: The paper discusses the role of small and common molecules, such are inducible nitric oxide synthase, arginase, heme oxygenase-1 or indoleamine-2,3-dioxygenase, the bioavailability of their substrates (L-arginine, tryptophan, heme) and the cytotoxic and regulatory actions of their small gaseous products (NO, CO), in regulation of transplantation reactions.