Die Bedeutung von Polymorphismen in MICA und anderen Genen des NKG2D-Signalwegs für die hämatopoetische Stammzelltransplantation

Zusammenfassung

Eine Reihe von retrospektiven klinischen Studien aus den letzten Jahren haben das hochpolymorphe Gen MICA als bedeutsam für das Ergebnis allogener hämatopoetischer Stammzelltransplantationen identifiziert. MICA ist ein durch zellulären Stress induzierbarer Ligand des aktivierenden NK-Rezeptors NKG2D. Der NKG2D-Signalweg triggert die zytotoxische Aktivität von NK-Zellen. NKG2D kann aber auch als costimulatorisches Molekül zur Aktivierung naiver CD8⁺-T-Zellen beitragen. Die MICA-Allele können abhängig von der kodierten Aminosäureposition 129 (Valin oder Methionin) in 2 Gruppen eingeteilt werden, deren Proteinprodukte sich in der Effizienz der Aktivierung des NKG2D-Signalwegs unterscheiden. Entsprechend zeigten einige Studien Effekte des MICA-129-Genotyps in Patienten auf die Risiken der Graft-versus-Host Disease (GvHD), eines Rezidivs einer malignen Grunderkrankung oder das Überleben nach Transplantation. Andere Studien berichteten ein geringeres Risiko für eine GvHD oder eine höhere Chance des Überlebens, wenn eine Übereinstimmung der MICA-Allele oder des MICA-129-Genotyps zwischen Spender und Empfänger vorlag. Funktionell relevante Polymorphismen im NKG2D kodierenden Gen KLRK1 und in ULBP6, einem weiteren NKG2D-Liganden, wurden ebenfalls als Einflussfaktoren für das Ergebnis der Transplantation identifiziert. Tierexperimente zeigten, dass der NKG2D-Signalweg sowohl GvHD als auch Graft-versus-Tumor-Reaktionen verstärkt. Durch eine nur vorübergehende Gabe von Anti-NKG2D-Antikörpern konnte selektiv die Schwere der GvHD vermindert werden. Die Polymorphismen von MICA und anderen Genen des NKG2D-Signalwegs könnten daher in Zukunft relevant werden für die Auswahl von besonders geeigneten Spendern oder für die Risikoadaptierung von Transplantationsprotokollen.

Abstract

Several retrospective clinical studies have recently identified the highly polymorphic gene MICA as relevant for the outcome of allogeneic hematopoietic stem cell transplantation. MICA is a ligand of the activating NK receptor NKG2D, which is induced by cellular stress. NKG2D triggers NK cell cytotoxicity and can contribute as a co-stimulatory molecule to the activation of naive CD8⁺-T cells. MICA alleles can be classified into two groups depending on the amino acid encoded at position 129 (valine or methionine) since the respective protein isoforms are distinguished by their efficacy to elicit NKG2D signaling. In accordance with these data, some studies showed effects of the MICA-129 genotype in patients on the risk of graft-versus-host disease (GvHD), relapse of malignancy or survival after transplantation. Other studies demonstrated a lower risk of GvHD or a higher probability of survival, if MICA alleles or the MICA-129 genotype was matched between donor and patient. Functionally relevant polymorphisms in KLRK1, the gene encoding NKG2D, and in ULBP6, a further NKG2D ligand, have been identified also to affect the outcome of the transplantation. Animal experiments demonstrated that the NKG2D signaling pathway augments GvHD and graft-versus-tumor reactions. A transient administration of anti-NKG2D antibodies could selectively reduce the severity of GvHD. Therefore, MICA and other genes of the NKG2D signaling pathway could become relevant for the selection of better suitable donors or for the development of better risk adapted transplantation protocols.

Schlüsselwörter

Graft-versus-Host Disease - Rezidiv - NK-Rezeptoren - NK-Zellen - T-Zellen

Key words

graft-versus-host disease - relapse - NK receptors - NK cells - T cells

• Literatur

• 1 Ghimire S, Weber D, Mavin E. et al. Pathophysiology of GvHD and other HSCT-related major complications. Front Immunol 2017; 8: 79
• 2 Gam R, Shah P, Crossland RE. et al. Genetic association of hematopoietic stem cell transplantation outcome beyond histocompatibility genes. Front Immunol 2017; 8: 380
• 3 Petersdorf EW. Role of major histocompatibility complex variation in graft-versus-host disease after hematopoietic cell transplantation. F1000Res 2017; 6: 617
• 4 Tiercy JM. How to select the best available related or unrelated donor of hematopoietic stem cells?. Haematologica 2016; 101: 680-687
• 5 Griffioen M, Van Bergen CA, Falkenburg JH. Autosomal minor histocompatibility antigens: how genetic variants create diversity in immune targets. Front Immunol 2016; 7: 100
• 6 Dickinson AM, Norden J, Li S. et al. Graft-versus-leukemia effect following hematopoietic stem cell transplantation for leukemia. Front Immunol 2017; 8: 496
• 7 Babor F, Fischer JC, Uhrberg M. The role of KIR genes and ligands in leukemia surveillance. Front Immunol 2013; 4: 27
• 8 Ruggeri L, Capanni M, Urbani E. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097-2100
• 9 Vivier E, Ugolini S, Blaise D. et al. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol 2012; 12: 239-252
• 10 Dickinson AM, Norden J. Non-HLA genomics: does it have a role in predicting haematopoietic stem cell transplantation outcome?. Int J Immunogenet 2015; 42: 229-238
• 11 Balavarca Y, Pearce K, Norden J. et al. Predicting survival using clinical risk scores and non-HLA immunogenetics. Bone Marrow Transplant 2015; 50: 1445-1452
• 12 Pearce KF, Balavarca Y, Norden J. et al. Impact of genomic risk factors on survival after haematopoietic stem cell transplantation for patients with acute leukaemia. Int J Immunogenet 2016; 43: 404-412
• 13 Middleton PG, Taylor PR, Jackson G. et al. Cytokine gene polymorphisms associating with severe acute graft-versus-host disease in HLA-identical sibling transplants. Blood 1998; 92: 3943-3948
• 14 Chien JW, Zhang XC, Fan W. et al. Evaluation of published single nucleotide polymorphisms associated with acute GVHD. Blood 2012; 119: 5311-5319
• 15 Harkensee C, Oka A, Onizuka M. et al. Single nucleotide polymorphisms and outcome risk in unrelated mismatched hematopoietic stem cell transplantation: an exploration study. Blood 2012; 119: 6365-6372
• 16 Boukouaci W, Busson M, Peffault De Latour R. et al. MICA-129 genotype, soluble MICA, and anti-MICA antibodies as biomarkers of chronic graft-versus-host disease. Blood 2009; 114: 5216-5224
• 17 Isernhagen A, Malzahn D, Viktorova E. et al. The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation. EMBO Mol Med 2015; 7: 1480-1502
• 18 Bahram S, Bresnahan M, Geraghty DE. et al. A second lineage of mammalian major histocompatibility complex class I genes. Proc Natl Acad Sci U S A 1994; 91: 6259-6263
• 19 Leelayuwat C, Townend DC, Degli-Esposti MA. et al. A new polymorphic and multicopy MHC gene family related to nonmammalian class I. Immunogenetics 1994; 40: 339-351
• 20 Carapito R, Bahram S. Genetics, genomics, and evolutionary biology of NKG2D ligands. Immunol Rev 2015; 267: 88-116
• 21 Groh V, Bahram S, Bauer S. et al. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci U S A 1996; 93: 12445-12450
• 22 Gasser S, Orsulic S, Brown EJ. et al. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 2005; 436: 1186-1190
• 23 Lanier LL. NKG2D receptor and its ligands in host defense. Cancer Immunol Res 2015; 3: 575-582
• 24 Bauer S, Groh V, Wu J. et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999; 285: 727-729
• 25 Billadeau DD, Upshaw JL, Schoon RA. et al. NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nat Immunol 2003; 4: 557-564
• 26 Groh V, Rhinehart R, Randolph-Habecker J. et al. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol 2001; 2: 255-260
• 27 Guerra N, Tan YX, Joncker NT. et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008; 28: 571-580
• 28 Wesselkamper SC, Eppert BL, Motz GT. et al. NKG2D is critical for NK cell activation in host defense against Pseudomonas aeruginosa respiratory infection. J Immunol 2008; 181: 5481-5489
• 29 Ogasawara K, Benjamin J, Takaki R. et al. Function of NKG2D in natural killer cell-mediated rejection of mouse bone marrow grafts. Nat Immunol 2005; 6: 938-945
• 30 Radosavljevic M, Cuillerier B, Wilson MJ. et al. A cluster of ten novel MHC class I related genes on human chromosome 6q24.2-q25.3. Genomics 2002; 79: 114-123
• 31 Choy MK, Phipps ME. MICA polymorphism: biology and importance in immunity and disease. Trends Mol Med 2010; 16: 97-106
• 32 Chen D, Gyllensten U. MICA polymorphism: biology and importance in cancer. Carcinogenesis 2014; 35: 2633-2642
• 33 Goto K, Kato N. MICA SNPs and the NKG2D system in virus-induced HCC. J Gastroenterol 2015; 50: 261-272
• 34 Ji M, Wang J, Yuan L. et al. MICA polymorphisms and cancer risk: a meta-analysis. Int J Clin Exp Med 2015; 8: 818-826
• 35 Wang Q, Zhou X. Associations of MICA polymorphisms with inflammatory rheumatic diseases. Open Rheumatol J 2015; 9: 94-100
• 36 Isernhagen A, Malzahn D, Bickeböller H. et al. Impact of the MICA-129Met/Val dimorphism on NKG2D-mediated biological functions and disease risks. Front Immunol 2016; 7: 588
• 37 Steinle A, Li P, Morris DL. et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics 2001; 53: 279-287
• 38 Nückel H, Switala M, Sellmann L. et al. The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia. Leukemia 2010; 24: 1152-1159
• 39 Hilpert J, Grosse-Hovest L, Grunebach F. et al. Comprehensive analysis of NKG2D ligand expression and release in leukemia: implications for NKG2D-mediated NK cell responses. J Immunol 2012; 189: 1360-1371
• 40 Lo PH, Urabe Y, Kumar V. et al. Identification of a functional variant in the MICA promoter which regulates MICA expression and increases HCV-related hepatocellular carcinoma risk. PLoS One 2013; 8: e61279
• 41 Shafi S, Vantourout P, Wallace G. et al. An NKG2D-mediated human lymphoid stress surveillance response with high interindividual variation. Sci Transl Med 2011; 3: 113ra124
• 42 Chitadze G, Bhat J, Lettau M. et al. Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications. Scand J Immunol 2013; 78: 120-129
• 43 Lü M, Xia B, Ge L. et al. Role of major histocompatibility complex class I-related molecules A*A5.1 allele in ulcerative colitis in Chinese patients. Immunology 2009; 128: e230-e236
• 44 Isernhagen A, Schilling D, Monecke S. et al. The MICA-129Met/Val dimorphism affects plasma membrane expression and shedding of the NKG2D ligand MICA. Immunogenetics 2016; 68: 109-123
• 45 Dulphy N, Haas P, Busson M. et al. An unusual CD56(bright) CD16(low) NK cell subset dominates the early posttransplant period following HLA-matched hematopoietic stem cell transplantation. J Immunol 2008; 181: 2227-2237
• 46 Gannage M, Buzyn A, Bogiatzi SI. et al. Induction of NKG2D ligands by gamma radiation and tumor necrosis factor-alpha may participate in the tissue damage during acute graft-versus-host disease. Transplantation 2008; 85: 911-915
• 47 Askar M, Sobecks R, Wang T. et al. MHC class I chain-related gene A (MICA) donor-recipient mismatches and MICA-129 polymorphism in unrelated donor hematopoietic cell transplantations has no impact on outcomes in acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant 2017; 23: 436-444
• 48 Gam R, Norden J, Crossland R. et al. MICA genotype, serum and expression level effects on the outcome of HSCT. Bone Marrow Transplant 2015; 50: S20-S21
• 49 Warren EH, Zhang XC, Li S. et al. Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT. Blood 2012; 120: 2796-2806
• 50 Malkki M, Gooley TA, Horowitz MM. et al. Mapping MHC-resident transplantation determinants. Biol Blood Marrow Transplant 2007; 13: 986-995
• 51 Petersdorf EW, Malkki M, Gooley TA. et al. MHC-resident variation affects risks after unrelated donor hematopoietic cell transplantation. Sci Transl Med 2012; 4: 144ra101
• 52 Petersdorf EW, Malkki M, Horowitz MM. et al. Mapping MHC haplotype effects in unrelated donor hematopoietic cell transplantation. Blood 2013; 121: 1896-1905
• 53 Fleischhauer K. Immunogenetics of HLA-DP – a new view of permissible mismatches. N Engl J Med 2015; 373: 669-672
• 54 Petersdorf EW, Malkki M, Oʼhuigin C. et al. High HLA-DP expression and graft-versus-host disease. N Engl J Med 2015; 373: 599-609
• 55 Kitcharoen K, Witt CS, Romphruk AV. et al. MICA, MICB, and MHC beta block matching in bone marrow transplantation: relevance to transplantation outcome. Hum Immunol 2006; 67: 238-246
• 56 Parmar S, Del Lima M, Zou Y. et al. Donor-recipient mismatches in MHC class I chain-related gene A in unrelated donor transplantation lead to increased incidence of acute graft-versus-host disease. Blood 2009; 114: 2884-2887
• 57 Anderson E, Grzywacz B, Wang H. et al. Limited role of MHC class I chain-related gene A (MICA) typing in assessing graft-versus-host disease risk after fully human leukocyte antigen-matched unrelated donor transplantation. Blood 2009; 114: 4753-4754 author reply 4754–4755
• 58 Askar M, Sun Y, Rybicki L. et al. Synergistic effect of major histocompatibility complex class I-related chain a and human leukocyte antigen-DPB1 mismatches in association with acute graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2014; 20: 1835-1840
• 59 Carapito R, Jung N, Kwemou M. et al. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD. Blood 2016; 128: 1979-1986
• 60 Fuerst D, Neuchel C, Niederwieser D. et al. Matching for the MICA-129 polymorphism is beneficial in unrelated hematopoietic stem cell transplantation. Blood 2016; 128: 3169-3176
• 61 Karimi MA, Bryson JL, Richman LP. et al. NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT. Blood 2015; 125: 3655-3663
• 62 Antoun A, Vekaria D, Salama RA. et al. The genotype of RAET1L (ULBP6), a ligand for human NKG2D (KLRK1), markedly influences the clinical outcome of allogeneic stem cell transplantation. Br J Haematol 2012; 159: 589-598
• 63 Zuo J, Willcox CR, Mohammed F. et al. A disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing by enhancing the stability of NKG2D ligand binding. Sci Signal 2017; 10: eaai8909
• 64 Isernhagen A, Malzahn D, Monecke S. et al. Functional consequences of genetic polymorphisms in the NKG2D receptor signaling pathway and putative gene interactions. Receptors Clin Investig 2016; 3: e1269
• 65 Hayashi T, Imai K, Morishita Y. et al. Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance. Cancer Res 2006; 66: 563-570
• 66 Furue H, Kumimoto H, Matsuo K. et al. Opposite impact of NKG2D genotype by lifestyle exposure to risk of aerodigestive tract cancer among Japanese. Int J Cancer 2008; 123: 181-186
• 67 Espinoza JL, Nguyen VH, Ichimura H. et al. A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to human papilloma virus-related cancers. Sci Rep 2016; 6: 39231
• 68 Espinoza JL, Takami A, Onizuka M. et al. NKG2D gene polymorphism has a significant impact on transplant outcomes after HLA-fully-matched unrelated bone marrow transplantation for standard risk hematologic malignancies. Haematologica 2009; 94: 1427-1434
• 69 Imai K, Hayashi T, Yamaoka M. et al. Effects of NKG2D haplotypes on the cell-surface expression of NKG2D protein on natural killer and CD8 T cells of peripheral blood among atomic-bomb survivors. Hum Immunol 2012; 73: 686-691
• 70 Espinoza JL, Takami A, Yoshioka K. et al. Human microRNA-1245 down-regulates the NKG2D receptor in natural killer cells and impairs NKG2D-mediated functions. Haematologica 2012; 97: 1295-1303
• 71 Baranwal AK, Mehra NK. Major histocompatibility complex class I chain-related A (MICA) molecules: relevance in solid organ transplantation. Front Immunol 2017; 8: 182
• 72 Risti M, Bicalho MD. MICA and NKG2D: is there an impact on kidney transplant outcome?. Front Immunol 2017; 8: 179
• 73 Zou Y, Mirbaha F, Lazaro A. et al. MICA is a target for complement-dependent cytotoxicity with mouse monoclonal antibodies and human alloantibodies. Hum Immunol 2002; 63: 30-39
• 74 Jinushi M, Hodi FS, Dranoff G. Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. Proc Natl Acad Sci U S A 2006; 103: 9190-9195
• 75 Boukouaci W, Al-Daccak R, Dulphy N. et al. Soluble MICA-NKG2D interaction upregulates IFN-gamma production by activated CD3–CD56+ NK cells: potential impact on chronic graft versus host disease. Hum Immunol 2013; 74: 1536-1541
• 76 Ansari M, Uppugunduri CR, Ferrari-Lacraz S. et al. The clinical relevance of pre-formed anti-HLA and anti-MICA antibodies after cord blood transplantation in children. PLoS One 2013; 8: e72141
• 77 Picardi A, Mengarelli A, Marino M. et al. Up-regulation of activating and inhibitory NKG2 receptors in allogeneic and autologous hematopoietic stem cell grafts. J Exp Clin Cancer Res 2015; 34: 98
• 78 Carapito R, Aouadi I, Ilias W. et al. Natural killer group 2, member D/NKG2D ligands in hematopoietic cell transplantation. Front Immunol 2017; 8: 368