Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Review Article

Editor's Choice - Free Access

Activation of Innate Immunity in Graft-versus-Host Disease: Implications for Novel Targets?

Zeiser R.

Author affiliations

Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg i.Br., Germany

Corresponding Author

Robert Zeiser, M.D.

Department of Hematology and Oncology

Freiburg University Medical Center

Hugstetterstr. 55, 79106 Freiburg i.Br., Germany

robert.zeiser@uniklinik-freiburg.de

Related Articles for ""

Oncol Res Treat 2015;38:239-243

Abstract

Acute graft-versus-host disease (GvHD) is mediated by alloreactive donor-derived T cells with a suitable T cell receptor recognizing recipient major histocompatibility complex or minor histocompatibility antigens. However, the process of T cell activation and tissue injury sensing is also dependent on innate immune cells and non-hematopoietic cells. Different cell types of the innate immune system have the ability to sense danger-associated and pathogen-associated molecular patterns via pattern recognition receptors which can be transmembrane Toll-like receptors or cytoplasmic nucleotide-binding oligomerization domain-like receptors. Infectious stimuli include bacterial, viral, and fungal components, while non-infectious stimuli can be components derived from damaged cells or extracellular matrix. A better understanding of the complex sensing and effector mechanisms of innate immune cells in GvHD may help to improve preventive and therapeutic strategies in GvHD.

© 2015 S. Karger GmbH, Freiburg


Introduction

Acute graft-versus-host disease (GvHD) is often preceded by tissue damage due to the conditioning regimen or infectious triggers. However, the disease can also develop in the absence of obvious infection when patients are treated with donor lymphocyte infusions. These observations suggest that the clinical symptoms of GvHD are caused by heterogeneous pathomechanisms that cannot be explained by a single disease model. However, multiple mouse studies and reports on GvHD in patients have indicated that besides the donor T cells as the disease-causing cell type, innate immune cells and the microbial flora participate in GvHD. Damage to barrier tissues such as skin or intestines allows for the translocation of bacterial or fungal antigens and consecutively exogenous and endogenous damage/pathogen-associated molecular patterns (DAMPs/PAMPs) which cause activation of pattern recognition receptors (PRRs) which can lead to the activation of neutrophils [1]. Examples of PRRs include Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) that result in the activation of different types of innate immune cells such as neutrophils, inflammatory monocytes, and macrophages.

Pattern Recognition Receptors in GvHD

The role of different TLRs in GvHD is controversial. Some investigators reported that TLR4 inactivation resulted in reduced dendritic cell (DC) activation leading to reduced GvHD severity [2], and treatment with heparin sulfate an endogenous TLR4 ligand enhanced GvHD [3]. Conversely, others reported that GvHD severity was unaffected by whether host antigen-presenting cells (APCs) were wild-type or deficient in MyD88, TRIF, or MyD88 and TRIF which represent crucial signaling pathways for TLRs [4]. However, the role of TLRs in GvHD is complicated by the fact that also tolerogenic innate immune cells may depend on TLR-based activation, such as for example myeloid-derived suppressor cells which are potent regulators of GvHD [5]. Consistent with a regulatory role of certain TLRs, pretreatment of mice with the TLR5 ligand flagellin resulted in reduced GvHD severity [6]. Administration of an agonist to TLR-7/8 induced indoleamine 2,3-dioxygenase (IDO) and reduced GvHD-related injury in the colon and ameliorated lethality [7]. Conversely, accelerated GvHD lethality by TLR9 ligation was reported [8]. Consistent with this report, genetic deficiency for TLR9 was associated with reduced GvHD severity [9,10]. Besides TLRs, cytoplasmic NOD proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses [11]. Penack et al. [12] showed that NOD2 deficiency in host hematopoietic cells exacerbated GvHD. Mechanistically it was shown that proliferation and activation of donor T cells was enhanced in NOD-deficient allogeneic bone marrow transplant recipients and that NOD2 plays a suppressive role in host APCs. In humans, NOD2/CARD15 polymorphisms have been identified as a risk factor for GvHD, although this finding was dependent on the investigated population [13]. PAMPs can be bacterial, viral, and fungal components, and recent evidence suggests a role of fungal antigens for GvHD [14,15]. Fungal motifs, including β-d-glucan and mannans, can activate the innate immune system via lectin receptors. C-type lectin receptors (CLRs) are defined by the presence of at least 1 C-type lectin-like domain. Of this larger superfamily, the single extracellular C-type lectin-like domain-containing receptors of the ‘dectin-1' and ‘dectin-2' clusters associate with signaling adaptors or possess integral intracellular signaling domains and are critical for the recognition of certain fungi [16]. Dectin-1 for example recognizes 1,3-beta-glucans and thereby plays a central role in the sensing of fungal antigens by innate immune cells [16]. The gut microbiota tightly regulates gut barrier function, and recent studies have demonstrated that probiotic bacteria can enhance barrier integrity. In this context, it was shown that Lactobacillus rhamnosus resulted in reduced translocation of enteric bacteria to the mesenteric lymph nodes and was associated with reduced severity of acute GvHD in mice [17]. Conversely, depletion of certain bacteria by treatment with an LPS inhibitor [18] or anti-endotoxin neutralizing antibodies [19] was associated with reduced GvHD severity. Most antibiotics cannot separate beneficial from harmful bacteria. However, prophylactic treatment with fluorchinolon antibiotics during the neutropenic phase for recipients of allogeneic hematopoietic cell transplantation (allo-HCT) is recommended by the European Conference on Infections and Leukaemia with a level of evidence AI [20,21]. Innate lymphoid cells (ILCs) are likely to be in direct contact with the invading bacteria following allo-HCT. Consistent with a role of ILCs in humans after allo-HCT, it was shown that NCR+ ILC3 cells, which are not present in the circulation of healthy persons, were detectable after induction chemotherapy [22]. This release could be related to intestinal tissue damage which needs to be clarified in future studies.

Danger Signals and Adenosine Metabolism

Nucleotides such as adenosine triphosphate (ATP), uridine triphosphate (UTP), adenosine diphosphate (ADP), or uridine diphosphate (UDP) are released by cells that experience stress or damage. The purine nucleoside ATP is highly concentrated in the cell while found in low concentrations in the extracellular space and therefore can serve as a potent danger signal when the cell membrane becomes permeable (reviewed in [23]). The activation of purinergic receptors is tightly regulated by ectonucleotidases, enzymes located on the cell surface which dephosphorylate extracellular nucleotides and eventually metabolize them to the respective nucleosides [24,25,26]. The ectonucleotidase family that metabolizes the first steps of ATP metabolism, the CD39 family (NTPDases), includes enzymes with common motifs in their protein sequences that are able to hydrolyze extracellular ATP and other nucleoside triphosphates (NTPs) as well as nucleoside diphosphates (NDPs) [27]. More downstream, purinergic signaling is modulated by ecto-5'-nucleotidase/CD73, a glycosylphosphatidylinositol-anchored cell membrane enzyme that catalyzes the dephosphorylation of extracellular nucleotide 5'-monophosphates to the respective nucleosides, in particular of 5'-AMP to adenosine [28]. CD73 deficiency of donor or recipient led to significantly aggravated GvHD with reduced survival of the recipient and increased GvHD histopathology score [29] which was later reproduced by another group [30]. Mechanistically, deletion of CD73 caused increased proliferation of alloreactive CD4+ and CD8+ T cells. Consistent with this finding, endogenous adenosine binding to the A2A-AR limited the expansion of alloreactive T cells and dampened the severity of acute GvHD [31,32]. This was consistent with the finding that activation of the A2A-AR reduced GvHD severity [33]. Increased levels of ATP were found in peritoneal fluids of humans and mice following GvHD or irradiation [34]. Binding of ATP to the purinergic receptor P2X7 leads to potassium efflux with consecutive activation of a multiprotein complex termed Nlrp3 inflammasome. ATP interaction with the purinergic receptor P2X7 on host APCs resulted in increased expression of co-stimulatory molecules CD80/CD86, phosphorylation of signal transducer and activator of transcription (STAT1), and production of inflammatory cytokines [34]. Chimeric mice that were genetically deficient for the P2X7 in host APCs were partially protected from GvHD indicating a critical role for these cells in sensing ATP following allo-HCT [34]. Besides P2X7 receptor-mediated activation, the Nlrp3 inflammasome can be activated by uric acid (UA) [35], a molecule found at high concentrations in patients that develop a tumor lysis syndrome when undergoing chemotherapy. Mice deficient in Nlrp3 or Asc experienced less severe GvHD [36]. Also, depletion of UA reduced IL-1β levels in the serum of mice developing GvHD and GvHD severity when given early after allo-HCT [36]. Consistent with this report in mice, in a recent phase I clinical study patients undergoing allo-HCT received recombinant urate oxidase for 5 consecutive days during conditioning [37]. Patients who developed acute GvHD had a higher level of serum UA in the pretransplantation period compared with those who did not (p < 0.001) [37], and the cumulative incidence of acute GvHD was significantly decreased in the UA depletion group compared to other patients [37]. However, another report found an association of low UA levels with GvHD [38]. Besides the proinflammatory roles for certain DAMPs, several lines of evidence have indicated a role for negative regulators of DAMP responses in controlling the severity of GvHD. Sialic acid-binding immunoglobulin-type lectins (Siglecs) are cell surface bound Ig-like lectins that bind sialic acid and function as counter regulators to immune activation [39]. A recent study showed that following total body irradiation for allo-HCT, Siglec-G is expressed on host APCs and can suppress activating signals from DAMPs [40]. Consistent with a negative regulatory role of Siglec-G, mice deficient for this molecule experienced increased GvHD severity. Conversely, enhanced Siglec-G signaling with CD24 in wild-type animals was protective against GvHD [40] indicating that promoting the effects of Siglecs could be exploited to mitigate GvHD severity.

Therapeutic Targeting of Innate Immune Activation

To manipulate the responses that drive GvHD, a major focus was given to donor-derived T cells. Consequently, the major prophylactic strategies target T cell activation, as for example cyclosporine A [41]. For GvHD treatment, however, the most frequently applied first-line treatment are corticosteroids [42] which target not only T cells but also function and homeostasis of APCs [43]. Therefore, strategies that target innate immune cells may be of added value to conventional drugs used to treat acute GvHD. Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in the signal transduction from TLRs, integrins, FcγR, dectin-1, and immunoreceptors such as TCR and BCR. Receptor activation and consecutive phosphorylation of ‘immunoreceptor tyrosine activation motifs' (ITAMs) allows for binding and activation of Syk [44]. Syk inhibition did not only impact alloreactive T cell activation but also reduced expression of co-stimulatory molecules on DCs and impaired their migration [45] which was connected to reduced GvHD severity. Recently, a second study confirmed the data and extended it to the chronic GvHD model [46]. Another strategy of targeting APC activation is epigenetic therapy [47]. This approach is based on the assumption that transcription factors that have translocated into the nucleus access anti-inflammatory target genes such as IDO if the epigenetic status of the DNA allows for it. Consistently, histone deacetylase inhibition, which allows for transcription of the respective target gene, was shown to modulate IDO-dependent APC functions and reduce GvHD [47]. These findings in the mouse model were successfully translated into a clinical setting and await further confirmation in a randomized multicenter study [48]. However, epigenetic therapy is not confined to APCs but also impacts regulatory [48,49] and conventional T cells [50], which could be an advantage given the aggressiveness of severe acute GvHD and the redundancy of different inflammatory pathways. Another approach that is likely to work on multiple levels of the immune response is JAK1/2 inhibition which was shown to reduce GvHD [51]. This approach was motivated by the fact that many of the cytokines involved in acute GvHD such as IL-6 and IL-12 use the JAK/STAT pathway to induce a proinflammatory response. Consistently, myeloid cell activation was reduced by JAK/STAT inhibition by AZD1480 in experimental autoimmune encephalomyelitis [52]. JAK3 inhibition with tofacitinib (CP-690550) [53] or genetic deficiency for JAK3 in donor T cells [54] attenuated GvHD in murine GvHD models. A central event in many pathways of innate immune activation is NF-kB signaling promoting DC maturation and production of immunogenic cytokines (e.g., IL-12, IL-6). Conversely, interfering with NF-kB activation in murine DCs renders them tolerogenic [55]. When APCs are activated, the transcription factors of alternative (RelB/p52) and canonical (c-Rel/p50) NF-kB pathways accumulate in nuclei [56]. Consistent with a functional role of RelB in recipient APCs, bone marrow chimeric mice lacking RelB in the hematopoietic system developed less severe GvHD [56]. Additionally, APCs from RelB-deficient mice are quantitatively reduced, induce less proliferation, and produce less cytokines compared with wild-type counterparts [56]. P2X7 is expressed by APCs, and lack of the purinergic receptor in recipient type APCs was connected to reduced GvHD severity [34]. Multiple preclinical studies have shown a role of the ATP/P2X7 axis in counteracting inflammation [34,57,58,59,60,61,62,63,64,65]. A phase II clinical study on P2X7 inhibition in rheumatoid arthritis showed a significant reduction in swollen and tender joint counts in the P2X7 inhibitor-treated group compared with placebo, whereas no effect on acute-phase response was observed [66]. The less impressive effects as compared to the data from animal models may be due to the fact that the DAMP ATP is released in higher amounts when severe tissue damage such as in sepsis of GvHD takes place. Another approach for targeting innate immune cells may be via microRNAs (miRs) that control the translation of inflammatory genes. The miRs interact with partially complementary sequences located primarily in the 3'UTR of their target mRNA which can result in either inhibition of translation or degradation of the mRNA which both prevent its translation into the protein/peptide. Multiple inflammation-promoting miRs have been investigated. MiR142-3p was shown to regulate APCs [67] in a model of endotoxin-induced mortality, which can be relevant in GvHD based on the reported role of LPS [18]. Most investigations on miRs in GvHD have focused on donor T cells. MiR142-3p in donor T cells was shown to regulate experimental GvHD via effects on their cell cycle [68]. Also a role of the miR146a/TRAF6 axis in donor T cells for GvHD was shown [69]. Here, genetic deletion of miR146a in donor T cells resulted in repression of TRAF6 with consecutively increased tumor necrosis factor transcription and more severe GvHD [69]. In the clinical setting, we observed that allo-HCT donors, who were homozygous for a miR-146a-impairing single nucleotide polymorphism conferred a trend towards a higher risk for severe GvHD grades III and IV in allo-HCT recipients [69]. Also, lack of miR155 in donor T cells was connected to reduced levels of GvHD, and miR155 was found in the intestinal tract of patients developing GvHD [70]. However, not only T cells were investigated with respect to a proinflammatory role of miRs in GvHD. We recently showed that miR-100 can regulate inflammatory neovascularization during GvHD [71] suggesting its role in endothelial cells. To exploit the pro- or anti-inflammatory functions of different miRs in acute GvHD, clinical-grade miR mimetics or antagomirs need to be developed. The multiple targets for GvHD treatment based on preclinical and early clinical trials are summarized in figure 1.

Fig. 1

Proposed mechanisms leading up to GvHD and the strategies to target them are shown. Red arrow: activation, dotted red arrow: hypothetical, blue line: inhibition, lightening: damage. UA: Uric acid, ATP: adenosine triphosphate.

http://www.karger.com/WebMaterial/ShowPic/131898

Disclosure Statement

The author has no conflict of interest to disclose.


References

  1. Schwab L, Goroncy L, Palaniyandi S, et al.: Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance GvHD via tissue damage. Nat Med 2014;20:648-654.
  2. Zhao Y, Liu Q, Yang L, et al.: TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Cell Mol Immunol 2013;10:165-175.
  3. Brennan TV, Lin L, Huang X, et al.: Heparan sulfate, an endogenous TLR4 agonist, promotes acute GvHD after allogeneic stem cell transplantation. Blood 2012;120:2899-2908.
  4. Li H, Matte-Martone C, Tan HS, et al.: Graft-versus-host disease is independent of innate signaling pathways triggered by pathogens in host hematopoietic cells. J Immunol 2011;186:230-241.
  5. Highfill SL, Rodriguez PC, Zhou Q, et al.: Bone marrow myeloid-derived suppressor cells (MDSCS) inhibit graft-versus-host disease (GvHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood 2010;116:5738-5747.
  6. Hossain MS, Jaye DL, Pollack BP, et al.: Flagellin, a TLR5 agonist, reduces graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients while enhancing antiviral immunity. J Immunol 2011;187:5130-5140.
  7. Jasperson LK, Bucher C, Panoskaltsis-Mortari A, et al.: Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GvHD) lethality. Blood 2009;114:5062-5070.
  8. Taylor PA, Ehrhardt MJ, Lees CJ, et al.: TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. Blood 2008;112:3508-3516.
  9. Calcaterra C, Sfondrini L, Rossini A, et al.: Critical role of TLR9 in acute graft-versus-host disease. J Immunol 2008;181:6132-6139.
  10. Heimesaat MM, Nogai A, Bereswill S, et al.: MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut 2010;59:1079-1087.
  11. Caruso R, Warner N, Inohara N, Núñez G: NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 2014;41:898-908.
  12. Penack O, Smith OM, Cunningham-Bussel A, et al.: NOD2 regulates hematopoietic cell function during graft-versus-host disease. J Exp Med 2009;206:2101-2110.
  13. Landfried K, Bataille F, Rogler G, et al.: Recipient NOD2/CARD15 status affects cellular infiltrates in human intestinal graft-versus-host disease. Clin Exp Immunol 2010;159:87-92.
  14. Van der Velden WJ, Netea MG, de Haan AF, et al.: Role of the mycobiome in human acute graft-versus-host disease. Biol Blood Marrow Transplant 2013;19:329-332.
  15. Van der Velden WJ, Plantinga TS, Feuth T, et al.: The incidence of acute graft-versus-host disease increases with candida colonization depending the dectin-1 gene status. Clin Immunol 2010;136:302-306.
  16. Dambuza IM, Brown GD: C-type lectins in immunity: recent developments. Curr Opin Immunol 2014;32:21-27.
  17. Gerbitz A, Schultz M, Wilke A, et al.: Probiotic effects on experimental graft-versus-host disease: let them eat yogurt. Blood 2004;103:4365-4367.
  18. Cooke K, Gerbitz A, Crawford JM, et al.: LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J Clin Invest 2001;102:1581-1589.
  19. Bayston K, Baumgartner JD, Clark P, Cohen J: Anti-endotoxin antibody for prevention of acute GvHD. Bone Marrow Transplant 1991;8:426-427.
    External Resources
  20. Cordonnier C, Calandra T: The first European conference on infections in leukaemia: why and how? Eur J Cancer 2007;suppl 5:2-4.
    External Resources
  21. Bucaneve G, Castagnola E, Viscoli C, et al.: Quinolone prophylaxis for bacterial infections in afebrile high risk neutropenic patients. Eur J Cancer 2007;suppl 5:5-12.
    External Resources
  22. Munneke JM, Björklund AT, Mjösberg JM, et al.: Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease. Blood 2014;124:812-821.
  23. Zeiser R, Penack O, Holler E, Idzko M: Danger signals activating innate immunity in graft-versus-host disease. J Mol Med 2011;89:833-845.
  24. Deaglio S, Robson SC: Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity. Adv Pharmacol 2011;61:301-332.
  25. Stagg J, Divisekera U, Duret H, et al.: CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res 2011;71:2892-2900.
  26. Sun X, Wu Y, Gao W, et al.: CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterology 2010;139:1030-1040.
  27. Knowles AF: The GDA1_CD39 superfamily: NTPDases with diverse functions. Purinergic Signal 2011;7:21-45.
  28. Thompson LF, Ruedi JM, Glass A, et al.: Antibodies to 5'-nucleotidase (CD73), a glycosyl-phosphatidylinositol-anchored protein, cause human peripheral blood t cells to proliferate. J Immunol 1989;143:1815-1821.
    External Resources
  29. Tsukamoto H, Chernogorova P, Ayata K, et al.: Deficiency of CD73/ecto-5'-nucleotidase in mice enhances acute graft-versus-host disease. Blood 2012;119:4554-4564.
  30. Wang L, Fan J, Chen S, et al.: Graft-versus-host disease is enhanced by selective CD73 blockade in mice. PLoS One 2013;8:e58397.
  31. Tsukamoto H, Chernogorova P, Ayata K, et al.: Deficiency of CD73/ecto-5'-nucleotidase in mice enhances acute graft-versus-host disease. Blood 2012;119:4554-4564.
  32. Thompson LF, Tsukamoto H, Chernogorova P, Zeiser R: A delicate balance: CD73-generated adenosine limits the severity of graft vs. host disease but also constrains the allogeneic graft vs. tumor effect. Oncoimmunology 2013;2:e22107.
  33. Lappas CM, Liu PC, Linden J, et al.: Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation. J Leukoc Biol 2010;87:345-354.
  34. Wilhelm K, Ganesan J, Müller T, et al.: Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nat Med 2010;12:1434-1438.
  35. Martinon F, Petrilli V, Mayor A, et al.: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237-241.
  36. Jankovic D, Ganesan J, Bscheider M, et al.: The Nlrp3 inflammasome regulates acute graft-versus-host disease. J Exp Med 2013;210:1899-1910.
  37. Yeh AC, Brunner AM, Spitzer TR, et al.: Phase I study of urate oxidase in the reduction of acute graft-versus-host disease after myeloablative allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2014;20:730-734.
  38. Ostendorf BN, Blau O, Uharek L, et al.: Association between low uric acid levels and acute graft-versus-host disease. Ann Hematol 2015;94:139-144.
  39. Crocker PR, Paulson JC, Varki A: Siglecs and their roles in the immune system. Nat Rev Immunol 2007;7:255-266.
  40. Toubai T, Hou G, Mathewson N, et al.: Siglec-G-CD24 axis controls the severity of graft-versus-host disease in mice. Blood 2014;123:3512-3523.
  41. Storb R, Deeg HJ, Whitehead J, et al.: Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986;314:729-735.
  42. Wolff D, Ayuk F, Elmaagacli A, et al.: Current practice in diagnosis and treatment of acute graft-versus-host disease: results from a survey among German-Austrian-Swiss hematopoietic stem cell transplant centers. Biol Blood Marrow Transplant 2013;19:767-776.
  43. Soulier A, Blois SM, Sivakumaran S, et al.: Cell-intrinsic regulation of murine dendritic cell function and survival by prereceptor amplification of glucocorticoid. Blood 2013;122:3288-3297.
  44. Mócsai A, Ruland J, Tybulewicz VL: The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 2010;10:387-402.
  45. Leonhardt F, Zirlik K, Buchner M, et al.: Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels. Leukemia 2012;26:1617-1629.
  46. Le Huu D, Kimura H, Date M, et al.: Blockade of Syk ameliorates the development of murine sclerodermatous chronic graft-versus-host disease. J Dermatol Sci 2014;74:214-221.
  47. Reddy P, Sun Y, Toubai T, et al.: Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent dc functions and regulates experimental graft-versus-host disease in mice. J Clin Invest 2008;118:2562-2573.
  48. Choi SW, Braun T, Chang L, et al.: Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol 2014;15:87-95.
  49. Choi J, Ritchey J, Prior JL, et al.: In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 2010;116:129-139.
  50. He S, Wang J, Kato K, et al.: Inhibition of histone methylation arrests ongoing graft-versus-host disease in mice by selectively inducing apoptosis of alloreactive effector T cells. Blood 2012;119:1274-1282.
  51. Spoerl S, Mathew NR, Bscheider M, et al.: Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014;123:3832-3842.
  52. Liu Y, Holdbrooks AT, De Sarno P, et al.: Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J Immunol 2014;192:59-72.
  53. Park HB, Oh K, Garmaa N, et al.: CP-690550, a Janus kinase inhibitor, suppresses CD4+ T-cell-mediated acute graft-versus-host disease by inhibiting the interferon-gamma pathway. Transplantation 2010;90:825-835.
  54. Hechinger AK, Smith BA, Flynn R, et al.: Therapeutic activity of multiple common gamma chain cytokine inhibition in acute and chronic GvHD. Blood 2015;125:570-580.
  55. Iruretagoyena MI, Sepúlveda SE, Lezana JP, et al.: Inhibition of nuclear factor-kappa b enhances the capacity of immature dendritic cells to induce antigen-specific tolerance in experimental autoimmune encephalomyelitis. J Pharmacol Exp Ther 2006;318:59-67.
  56. MacDonald KP, Kuns RD, Rowe V, et al.: Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVDH. Blood 2007;109:5049.
  57. Vergani A, Fotino C, D'Addio F, et al.: Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection. Diabetes 2013;62:1665-1675.
  58. Vergani A, Tezza S, D'Addio F, et al.: Long-term heart transplant survival by targeting the ionotropic purinergic receptor p2x7. Circulation 2013;127:463-475.
  59. Kurashima Y, Amiya T, Nochi T, et al.: Extracellular ATP mediates mast cell-dependent intestinal inflammation through p2x7 purinoceptors. Nat Commun 2012;3:1034.
  60. Weber FC, Esser PR, Müller T, et al.: Lack of the purinergic receptor p2x(7) results in resistance to contact hypersensitivity. J Exp Med 2010;207:2609-2619.
  61. Cicko S, Lucattelli M, Muller T, et al.: Purinergic receptor inhibition prevents the development of smoke-induced lung injury and emphysema. J Immunol 2010;185:688-697.
  62. Kawamura H, Aswad F, Minagawa M, et al.: P2x7 receptors regulate NKT cells in autoimmune hepatitis. J Immunol 2006;176:2152-2160.
  63. Sharp AJ, Polak PE, Simonini V, et al.: P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis. J Neuroinflammation 2008;5:33-37.
  64. Zhao J, Wang H, Dai C, et al.: P2x7 blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway. Arthritis Rheum 2013;65:3176-3185.
  65. Hoque R, Sohail M, Malik A, et al.: TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis. Gastoenterology 2011;141:358-369.
  66. Keystone EC, Wang MM, Layton M, et al.: Clinical evaluation of the efficacy of the P2x7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann Rheum Dis 2012;71:1630-1635.
  67. Sun Y, Varambally S, Maher CA, et al.: Targeting of microrna-142-3p in dendritic cells regulates endotoxin-induced mortality. Blood 2011;117:6172-6183.
  68. Sun Y, Oravecz-Wilson K, Saunders T, et al.: Atypical E2F dependent dysregulation of cell cycling by microRNA-142 regulates T-cell responses and experimental graft-versus-host disease. Blood 2013;122:abstr 136.
  69. Stickel N, Prinz G, Pfeifer D, et al.: MiR-146a regulates the TRAF6/TNF-axis in donor t cells during GVDH. Blood 2014;124:2586-2595.
  70. Ranganathan P, Heaphy CE, Costinean S, et al.: Regulation of acute graft-versus-host disease by microRNA-155. Blood 2012;119:4786-4797.
  71. Leonhardt F, Grundmann S, Behe M, et al.: Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100. Blood 2013;121:3307-3318.

Author Contacts

Robert Zeiser, M.D.

Department of Hematology and Oncology

Freiburg University Medical Center

Hugstetterstr. 55, 79106 Freiburg i.Br., Germany

robert.zeiser@uniklinik-freiburg.de


Article / Publication Details

First-Page Preview
Abstract of Review Article

Received: January 16, 2015
Accepted: March 02, 2015
Published online: March 17, 2015
Issue release date: May 2015

Number of Print Pages: 5
Number of Figures: 1
Number of Tables: 0

ISSN: 2296-5270 (Print)
eISSN: 2296-5262 (Online)

For additional information: https://www.karger.com/ORT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Schwab L, Goroncy L, Palaniyandi S, et al.: Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance GvHD via tissue damage. Nat Med 2014;20:648-654.
  2. Zhao Y, Liu Q, Yang L, et al.: TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Cell Mol Immunol 2013;10:165-175.
  3. Brennan TV, Lin L, Huang X, et al.: Heparan sulfate, an endogenous TLR4 agonist, promotes acute GvHD after allogeneic stem cell transplantation. Blood 2012;120:2899-2908.
  4. Li H, Matte-Martone C, Tan HS, et al.: Graft-versus-host disease is independent of innate signaling pathways triggered by pathogens in host hematopoietic cells. J Immunol 2011;186:230-241.
  5. Highfill SL, Rodriguez PC, Zhou Q, et al.: Bone marrow myeloid-derived suppressor cells (MDSCS) inhibit graft-versus-host disease (GvHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood 2010;116:5738-5747.
  6. Hossain MS, Jaye DL, Pollack BP, et al.: Flagellin, a TLR5 agonist, reduces graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients while enhancing antiviral immunity. J Immunol 2011;187:5130-5140.
  7. Jasperson LK, Bucher C, Panoskaltsis-Mortari A, et al.: Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GvHD) lethality. Blood 2009;114:5062-5070.
  8. Taylor PA, Ehrhardt MJ, Lees CJ, et al.: TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. Blood 2008;112:3508-3516.
  9. Calcaterra C, Sfondrini L, Rossini A, et al.: Critical role of TLR9 in acute graft-versus-host disease. J Immunol 2008;181:6132-6139.
  10. Heimesaat MM, Nogai A, Bereswill S, et al.: MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut 2010;59:1079-1087.
  11. Caruso R, Warner N, Inohara N, Núñez G: NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 2014;41:898-908.
  12. Penack O, Smith OM, Cunningham-Bussel A, et al.: NOD2 regulates hematopoietic cell function during graft-versus-host disease. J Exp Med 2009;206:2101-2110.
  13. Landfried K, Bataille F, Rogler G, et al.: Recipient NOD2/CARD15 status affects cellular infiltrates in human intestinal graft-versus-host disease. Clin Exp Immunol 2010;159:87-92.
  14. Van der Velden WJ, Netea MG, de Haan AF, et al.: Role of the mycobiome in human acute graft-versus-host disease. Biol Blood Marrow Transplant 2013;19:329-332.
  15. Van der Velden WJ, Plantinga TS, Feuth T, et al.: The incidence of acute graft-versus-host disease increases with candida colonization depending the dectin-1 gene status. Clin Immunol 2010;136:302-306.
  16. Dambuza IM, Brown GD: C-type lectins in immunity: recent developments. Curr Opin Immunol 2014;32:21-27.
  17. Gerbitz A, Schultz M, Wilke A, et al.: Probiotic effects on experimental graft-versus-host disease: let them eat yogurt. Blood 2004;103:4365-4367.
  18. Cooke K, Gerbitz A, Crawford JM, et al.: LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J Clin Invest 2001;102:1581-1589.
  19. Bayston K, Baumgartner JD, Clark P, Cohen J: Anti-endotoxin antibody for prevention of acute GvHD. Bone Marrow Transplant 1991;8:426-427.
    External Resources
  20. Cordonnier C, Calandra T: The first European conference on infections in leukaemia: why and how? Eur J Cancer 2007;suppl 5:2-4.
    External Resources
  21. Bucaneve G, Castagnola E, Viscoli C, et al.: Quinolone prophylaxis for bacterial infections in afebrile high risk neutropenic patients. Eur J Cancer 2007;suppl 5:5-12.
    External Resources
  22. Munneke JM, Björklund AT, Mjösberg JM, et al.: Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease. Blood 2014;124:812-821.
  23. Zeiser R, Penack O, Holler E, Idzko M: Danger signals activating innate immunity in graft-versus-host disease. J Mol Med 2011;89:833-845.
  24. Deaglio S, Robson SC: Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity. Adv Pharmacol 2011;61:301-332.
  25. Stagg J, Divisekera U, Duret H, et al.: CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res 2011;71:2892-2900.
  26. Sun X, Wu Y, Gao W, et al.: CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterology 2010;139:1030-1040.
  27. Knowles AF: The GDA1_CD39 superfamily: NTPDases with diverse functions. Purinergic Signal 2011;7:21-45.
  28. Thompson LF, Ruedi JM, Glass A, et al.: Antibodies to 5'-nucleotidase (CD73), a glycosyl-phosphatidylinositol-anchored protein, cause human peripheral blood t cells to proliferate. J Immunol 1989;143:1815-1821.
    External Resources
  29. Tsukamoto H, Chernogorova P, Ayata K, et al.: Deficiency of CD73/ecto-5'-nucleotidase in mice enhances acute graft-versus-host disease. Blood 2012;119:4554-4564.
  30. Wang L, Fan J, Chen S, et al.: Graft-versus-host disease is enhanced by selective CD73 blockade in mice. PLoS One 2013;8:e58397.
  31. Tsukamoto H, Chernogorova P, Ayata K, et al.: Deficiency of CD73/ecto-5'-nucleotidase in mice enhances acute graft-versus-host disease. Blood 2012;119:4554-4564.
  32. Thompson LF, Tsukamoto H, Chernogorova P, Zeiser R: A delicate balance: CD73-generated adenosine limits the severity of graft vs. host disease but also constrains the allogeneic graft vs. tumor effect. Oncoimmunology 2013;2:e22107.
  33. Lappas CM, Liu PC, Linden J, et al.: Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation. J Leukoc Biol 2010;87:345-354.
  34. Wilhelm K, Ganesan J, Müller T, et al.: Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nat Med 2010;12:1434-1438.
  35. Martinon F, Petrilli V, Mayor A, et al.: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237-241.
  36. Jankovic D, Ganesan J, Bscheider M, et al.: The Nlrp3 inflammasome regulates acute graft-versus-host disease. J Exp Med 2013;210:1899-1910.
  37. Yeh AC, Brunner AM, Spitzer TR, et al.: Phase I study of urate oxidase in the reduction of acute graft-versus-host disease after myeloablative allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2014;20:730-734.
  38. Ostendorf BN, Blau O, Uharek L, et al.: Association between low uric acid levels and acute graft-versus-host disease. Ann Hematol 2015;94:139-144.
  39. Crocker PR, Paulson JC, Varki A: Siglecs and their roles in the immune system. Nat Rev Immunol 2007;7:255-266.
  40. Toubai T, Hou G, Mathewson N, et al.: Siglec-G-CD24 axis controls the severity of graft-versus-host disease in mice. Blood 2014;123:3512-3523.
  41. Storb R, Deeg HJ, Whitehead J, et al.: Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986;314:729-735.
  42. Wolff D, Ayuk F, Elmaagacli A, et al.: Current practice in diagnosis and treatment of acute graft-versus-host disease: results from a survey among German-Austrian-Swiss hematopoietic stem cell transplant centers. Biol Blood Marrow Transplant 2013;19:767-776.
  43. Soulier A, Blois SM, Sivakumaran S, et al.: Cell-intrinsic regulation of murine dendritic cell function and survival by prereceptor amplification of glucocorticoid. Blood 2013;122:3288-3297.
  44. Mócsai A, Ruland J, Tybulewicz VL: The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 2010;10:387-402.
  45. Leonhardt F, Zirlik K, Buchner M, et al.: Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels. Leukemia 2012;26:1617-1629.
  46. Le Huu D, Kimura H, Date M, et al.: Blockade of Syk ameliorates the development of murine sclerodermatous chronic graft-versus-host disease. J Dermatol Sci 2014;74:214-221.
  47. Reddy P, Sun Y, Toubai T, et al.: Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent dc functions and regulates experimental graft-versus-host disease in mice. J Clin Invest 2008;118:2562-2573.
  48. Choi SW, Braun T, Chang L, et al.: Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol 2014;15:87-95.
  49. Choi J, Ritchey J, Prior JL, et al.: In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 2010;116:129-139.
  50. He S, Wang J, Kato K, et al.: Inhibition of histone methylation arrests ongoing graft-versus-host disease in mice by selectively inducing apoptosis of alloreactive effector T cells. Blood 2012;119:1274-1282.
  51. Spoerl S, Mathew NR, Bscheider M, et al.: Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014;123:3832-3842.
  52. Liu Y, Holdbrooks AT, De Sarno P, et al.: Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J Immunol 2014;192:59-72.
  53. Park HB, Oh K, Garmaa N, et al.: CP-690550, a Janus kinase inhibitor, suppresses CD4+ T-cell-mediated acute graft-versus-host disease by inhibiting the interferon-gamma pathway. Transplantation 2010;90:825-835.
  54. Hechinger AK, Smith BA, Flynn R, et al.: Therapeutic activity of multiple common gamma chain cytokine inhibition in acute and chronic GvHD. Blood 2015;125:570-580.
  55. Iruretagoyena MI, Sepúlveda SE, Lezana JP, et al.: Inhibition of nuclear factor-kappa b enhances the capacity of immature dendritic cells to induce antigen-specific tolerance in experimental autoimmune encephalomyelitis. J Pharmacol Exp Ther 2006;318:59-67.
  56. MacDonald KP, Kuns RD, Rowe V, et al.: Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVDH. Blood 2007;109:5049.
  57. Vergani A, Fotino C, D'Addio F, et al.: Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection. Diabetes 2013;62:1665-1675.
  58. Vergani A, Tezza S, D'Addio F, et al.: Long-term heart transplant survival by targeting the ionotropic purinergic receptor p2x7. Circulation 2013;127:463-475.
  59. Kurashima Y, Amiya T, Nochi T, et al.: Extracellular ATP mediates mast cell-dependent intestinal inflammation through p2x7 purinoceptors. Nat Commun 2012;3:1034.
  60. Weber FC, Esser PR, Müller T, et al.: Lack of the purinergic receptor p2x(7) results in resistance to contact hypersensitivity. J Exp Med 2010;207:2609-2619.
  61. Cicko S, Lucattelli M, Muller T, et al.: Purinergic receptor inhibition prevents the development of smoke-induced lung injury and emphysema. J Immunol 2010;185:688-697.
  62. Kawamura H, Aswad F, Minagawa M, et al.: P2x7 receptors regulate NKT cells in autoimmune hepatitis. J Immunol 2006;176:2152-2160.
  63. Sharp AJ, Polak PE, Simonini V, et al.: P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis. J Neuroinflammation 2008;5:33-37.
  64. Zhao J, Wang H, Dai C, et al.: P2x7 blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway. Arthritis Rheum 2013;65:3176-3185.
  65. Hoque R, Sohail M, Malik A, et al.: TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis. Gastoenterology 2011;141:358-369.
  66. Keystone EC, Wang MM, Layton M, et al.: Clinical evaluation of the efficacy of the P2x7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann Rheum Dis 2012;71:1630-1635.
  67. Sun Y, Varambally S, Maher CA, et al.: Targeting of microrna-142-3p in dendritic cells regulates endotoxin-induced mortality. Blood 2011;117:6172-6183.
  68. Sun Y, Oravecz-Wilson K, Saunders T, et al.: Atypical E2F dependent dysregulation of cell cycling by microRNA-142 regulates T-cell responses and experimental graft-versus-host disease. Blood 2013;122:abstr 136.
  69. Stickel N, Prinz G, Pfeifer D, et al.: MiR-146a regulates the TRAF6/TNF-axis in donor t cells during GVDH. Blood 2014;124:2586-2595.
  70. Ranganathan P, Heaphy CE, Costinean S, et al.: Regulation of acute graft-versus-host disease by microRNA-155. Blood 2012;119:4786-4797.
  71. Leonhardt F, Grundmann S, Behe M, et al.: Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100. Blood 2013;121:3307-3318.
ppt logo Download Images (.pptx)


Figures
Thumbnail

Tables