Acute graft-versus-host disease (aGvHD) is a major complication after hematopoietic stem cell transplantation (HSCT) and severity of aGvHD is associated with biological and genetic factors related to donors and recipients. Studies on inflammatory pathways involved in aGvHD have shown a significant impact of the gut microflora on aGvHD development giving increasing evidence in the understanding of the response of innate and adaptive immunity to microbial products. Cytokine deregulation may increase or reduce the risk of aGvHD. Damage of tissues affected by aGvHD reflects the immunological cascade of events in this disease. 1. Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a clinically accepted procedure in some hematological malignances, aplastic anemia, and inborn errors. It is rather a complex procedure, associated with both the adverse effect aGvHD and with the presence of beneficial alloreactivity, as it is graft versus leukemia or versus cells with inborn error reaction [1–4]. Alloreactivity influences both hematological and immunological recovery. Both alloreactivity and recovery of blood cells take place in an environment full of microbial agents in a latent form or colonizing/invading the host. Innate and adaptive immunity competence prior to and after HSCT secure an event-free course after HSCT with respect to that. 1.1. Biology of Acute GvHD Damage of the gastrointestinal tract during the acute phase of GvHD plays a major pathophysiological role in the amplification of this systemic disease. Several experimental and clinical observations highlight the role of effector cells of the immune system migration into the skin and gastrointestinal tract in the pathobiology of aGvHD [5]. Mice are the most often used animal model of GvHD. Differences in age, sex, genetic matching, and also gut microbiota of the mice are found to be the main players in pathophysiology of GvHD [6]. One of the first reports describing the microbial environment of the recipient as an important cofactor of gut aGvHD development was presented by Van Bekkum et al. [7, 8]. In their studies they compared the fate of conventionally and germ-free housed mice after whole-body irradiation and MHC incompatible bone marrow cell transplantation. Enteric aGvHD was less frequent in germ-free mice and in mice receiving antibiotic prophylaxis as compared to conventionally transplanted animals. The authors concluded that antigenic epitopes of microorganisms shared with gut epithelial cells may promote alloreactivity. These observations indicated that lymphocytes
References
[1]
S. W. Choi, J. E. Levine, and J. L. M. Ferrara, “Pathogenesis and management of graft-versus-host disease,” Immunology and Allergy Clinics of North America, vol. 30, no. 1, pp. 75–101, 2010.
[2]
A. J. Barrett, “Understanding and harnessing the graft-versus-leukaemia effect,” British Journal of Haematology, vol. 142, no. 6, pp. 877–888, 2008.
[3]
Y. Lu, C. R. Giver, and A. Sharma, “IFN-gamma and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity,” Blood, vol. 119, pp. 1075–1085, 2012.
[4]
V. K. Prasad and J. Kurtzberg, “Cord blood and bone marrow transplantation in inherited metabolic diseases: scientific basis, current status and future directions,” British Journal of Haematology, vol. 148, no. 3, pp. 356–372, 2010.
[5]
R. Sackstein, “A revision of Billingham's tenets: the central role of lymphocyte migration in acute graft-versus-host disease,” Biology of Blood and Marrow Transplantation, vol. 12, no. 1, pp. 2–8, 2006.
[6]
J. L. Ferrara, J. E. Levine, P. Reddy, and E. Holler, “Graft-versus-host disease,” The Lancet, vol. 373, no. 9674, pp. 1550–1561, 2009.
[7]
D. W. Van Bekkum and S. Knaan, “Role of bacterial microflora in development of intestinal lesions from graft versus host reaction,” Journal of the National Cancer Institute, vol. 58, no. 3, pp. 787–790, 1977.
[8]
D. W. Van Bekkum, J. Roodenburg, P. J. Heidt, and D. Van Der Waaij, “Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora,” Journal of the National Cancer Institute, vol. 52, no. 2, pp. 401–404, 1974.
[9]
G. R. Hill and J. L. M. Ferrara, “The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation,” Blood, vol. 95, no. 9, pp. 2754–2759, 2000.
[10]
B. R. Blazar, W. J. Murphy, and M. Abedi, “Advances in graft-versus-host disease biology and therapy,” Nature Reviews Immunology, vol. 12, pp. 443–458, 2012.
[11]
C. Calcaterra, L. Sfondrini, A. Rossini et al., “Critical role of TLR9 in acute graft-versus-host disease,” Journal of Immunology, vol. 181, no. 9, pp. 6132–6139, 2008.
[12]
O. Penack, E. Holler, and M. R. M. Van Den Brink, “Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors,” Blood, vol. 115, no. 10, pp. 1865–1872, 2010.
[13]
M. M. Heimesaat, A. Nogai, S. Bereswill et al., “MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease,” Gut, vol. 59, no. 8, pp. 1079–1087, 2010.
[14]
T. Imado, T. Iwasaki, S. Kitano et al., “The protective role of host Toll-like receptor-4 in acute graft-versus-host disease,” Transplantation, vol. 90, no. 10, pp. 1063–1070, 2010.
[15]
A. Gerbitz, M. Schultz, A. Wilke et al., “Probiotic effects on experimental graft-versus-host disease: let them eat yogurt,” Blood, vol. 103, no. 11, pp. 4365–4367, 2004.
[16]
R. R. Jenq, C. Ubeda, and Y. Taur, “Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation,” Journal of Experimental Medicine, vol. 209, pp. 903–911, 2012.
[17]
D. W. Beelen, A. Elmaagacli, K. D. Müller, H. Hirche, and U. W. Schaefer, “Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft- versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and long-term follow-up of an open-label prospective randomized trial,” Blood, vol. 93, no. 10, pp. 3267–3275, 1999.
[18]
D. Berrebi, R. Maudinas, J. P. Hugot et al., “Card15 gene overexpression in mononuclear and epithelial cells of the inflamed Crohn's disease colon,” Gut, vol. 52, no. 6, pp. 840–846, 2003.
[19]
A. Madrigal and B. E. Shaw, “Immunogenetic factors in donors and patients that affect the outcome of hematopoietic stem cell transplantation,” Blood Cells, Molecules, and Diseases, vol. 40, no. 1, pp. 40–43, 2008.
[20]
E. Holler, G. Rogler, H. Herfarth et al., “Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation,” Blood, vol. 104, no. 3, pp. 889–894, 2004.
[21]
K. Bogunia-Kubik, E. Jaskula, D. D？ubek, A. Wójtowicz, and A. Lange, “SNP8 of the NOD2/CARD15 gene and acute GvHD contribute to CMV reactivation after allogeneic haematopoietic stem cell transplantation,” Bone Marrow Transplantation, vol. 46, no. 1, supplement, p. S82, 2011.
[22]
A. Lange, K. Suchnicki, S. Mizia, P. Czajka, A. Lach, and D. Dlubek, “Low blood levels of Th17 cells are seen in patients with aGvHD and associate with rather poor survival post HSCT,” Blood, vol. 118, abstract 4079, 2011.
[23]
P. Reddy, “Pathophysiology of acute graft-versus-host disease,” Hematological Oncology, vol. 21, no. 4, pp. 149–161, 2003.
[24]
A. Klimczak and A. Lange, “Apoptosis of keratinocytes is associated with infiltration of CD8+ lymphocytes and accumulation of Ki67 antigen,” Bone Marrow Transplantation, vol. 26, no. 10, pp. 1077–1082, 2000.
[25]
T. A. Weaver and A. D. Kirk, “Alemtuzumab,” Transplantation, vol. 84, no. 12, pp. 1545–1547, 2007.
[26]
G. R. Hill, J. M. Crawford, K. R. Cooke, Y. S. Brinson, L. Pan, and J. L. M. Ferrara, “Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines,” Blood, vol. 90, no. 8, pp. 3204–3213, 1997.
[27]
A. Lange, L. Karabon, A. Klimczak et al., “Serum interferon-γ and C-reactive protein levels as predictors of acute graft-vs-host disease in allogeneic hematopoietic precursor cell (marrow or peripheral blood progenitor cells) recipients,” Transplantation Proceedings, vol. 28, no. 6, pp. 3522–3525, 1996.
[28]
S. Murphy and V. H. Nguyen, “Role of gut microbiota in graft-versus-host disease,” Leukemia & Lymphoma, vol. 52, pp. 1844–1856, 2011.
[29]
L. Karabon, A. Moniewska, A. Laba, C. Swider, and A. Lange, “IL-6 is present in sera of bone marrow-transplanted patients in aplastic period and high levels of IL-6 during acute graft-versus-host disease are associated with severe gut symptoms,” Annals of the New York Academy of Sciences, vol. 762, pp. 439–442, 1995.
[30]
S. Fuji, S. W. Kim, T. Fukuda et al., “Preengraftment serum C-reactive protein (CRP) value may predict acute graft-versus-host disease and nonrelapse mortality after allogeneic hematopoietic stem cell transplantation,” Biology of Blood and Marrow Transplantation, vol. 14, no. 5, pp. 510–517, 2008.
[31]
J. H. Niess, F. Leith？user, G. Adler, and J. Reimann, “Commensal gut flora drives the expansion of proinflammatory CD4 T cells in the colonic lamina propria under normal and inflammatory conditions,” Journal of Immunology, vol. 180, no. 1, pp. 559–568, 2008.
[32]
J. S. Serody and G. R. Hill, “The IL-17 differentiation pathway and its role in transplant outcome,” Biology of Blood and Marrow Transplantation, vol. 18, pp. S56–S61, 2012.
[33]
E. Bettelli, Y. Carrier, W. Gao et al., “Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells,” Nature, vol. 441, no. 7090, pp. 235–238, 2006.
[34]
H. Chung and D. L. Kasper, “Microbiota-stimulated immune mechanisms to maintain gut homeostasis,” Current Opinion in Immunology, vol. 22, no. 4, pp. 455–460, 2010.
[35]
A. Klimczak, A. Lach, E. Jaskula, and A. Lange, “IL-17 and CCR6 positive cells are present in the skin and gut with toxic lesions and even more pronounced in aGvHD,” Bone Marrow Transplantation, vol. 46, supplement 1, p. S102, 2011.
[36]
R. Varona, V. Cadenas, L. Gómez, C. Martínez-A, and G. Márquez, “CCR6 regulates CD4+ T-cell-mediated acute graft-versus-host disease responses,” Blood, vol. 106, no. 1, pp. 18–26, 2005.
[37]
C. Wang, S. G. Kang, J. Lee, Z. Sun, and C. H. Kim, “The roles of CCR6 in migration of Th17 cells and regulation of effector T-cell balance in the gut,” Mucosal Immunology, vol. 2, no. 2, pp. 173–183, 2009.
[38]
E. Dander, A. Balduzzi, G. Zappa et al., “Interleukin-17-producing t-helper cells as new potential player mediating graft-versus-host disease in patients undergoing allogeneic stem-cell transplantation,” Transplantation, vol. 88, no. 11, pp. 1261–1272, 2009.
[39]
D. Dlubek, E. Turlej, M. Sedzimirska, J. Lange, and A. Lange, “Interleukin-17-producing cells increase among CD4+ lymphocytes before overt manifestation of acute graft-versus-host disease,” Transplantation Proceedings, vol. 42, no. 8, pp. 3277–3279, 2010.
