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96Cellular Therapy and Transplantation (CTT). Vol. 6, No. 2 (19), 2017 doi: 1018620/ctt-1866-8836-2017-6-2-36-51 Submitted: 07 June 2017, accepted: 30 June 2017
Beyond HLA system: non-HLA gene alleles of donor origin may influence risk of immune allo-HSCT complications
Alexey B. Chukhlovin
R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
Prof. Alexey B.Chukhlovin, R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The St. Petersburg State I. Pavlov Medical University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Summary
This review article concerns genetic predisposal for some severe immune complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) which are mostly dependent on donor/recipient differences in the HLA set and on the so-called minor compatibility factors, e.g., certain HLA-G alleles and other immune-re -lated proteins (TNF-a, IL1-^, IL-2, -6, 10 and their receptors) associated with overall survival, graft rejection or acute graft-versus-host disease. Moreover, HSCT is a complex procedure with multiple cytotoxic agents used at conditioning therapy, and immunosuppressive drugs applied at different stages of posttransplant period. The minimal nucleotide differences in functionally active genes may cause sufficient changes in cell damage and recovery after HSCT. These polymorphic alleles could increase or diminish biological action of different enzymes, receptors, transporters, transcription factors etc. Therefore, distinct polymorphic gene alleles exhibiting high-or low-producing activities may be associated with major complications of HSCT and survival in HSC recipients.
Current studies on numerous effects of non-HLA gene polymorphisms in the donor/recipient pairs allowed us
to make the following conclusions: 1) the majority of functionally active gene alleles controlling kinetics of cytotoxic drugs was mainly by recipient origin, normally being expressed in liver, spleen and target cells of blood system; 2) by contrary, gene alleles controlling immune factors (cytokines, their receptors etc.), associated with acute graft-versus-host disease were mostly, of donor origin, being more common than appropriate recipient alleles.
This donor predominance of allelic SNPs should be taken into account when planning haploidentical transplants and infusions of donor lymphoid cells in immunotherapy of tumors. For example, one may expect more expressed graft-versus-leukemia effect from the donor T cells exhibiting more active gene alleles (e.c., IL-6, IL-7R, MMP-1 et al.). Moreover, these protein products may be targeted by specific inhibitors to prevent excessive aGVHD.
Keywords
Hematopoietic stem cell transplantation, outcomes, functional gene polymorphisms, immune complications, pharmacokinetics.
Introduction
Common complications, relapse rates and clinical outcomes in allogeneic hematopoietic stem cell transplantation (al-lo-HSCT) settings are primarily dependent on donor/recipient differences in HLA system. Highly complex polymorphic patterns of HLA genes at chromosome 6 are historically in focus of HSCT studies being carefully tested (Franca et al., 2015). In addition, gene variants of the so-called minor compatibility factors, e.g., certain HLA-G alleles and other immune-related proteins may be also associated with overall survival, graft rejection or acute graft-versus-host disease (Mullighan, Petersdorf, 2006). This list includes a series of well-known cytokines as TNF-a, IL1-p, IL-2, -6, 10 and their receptors on target cell populations. Numerous polymorphisms were revealed in the genes encoding specific proteins (cytokines, chemokines and their receptors on target cells) active in immunity. The genes encoding foreign antigen-binding receptors (NOD2, TLR) and cell contact proteins may also exhibit functional polymorphisms.
Another class of non-MHC genes affecting HCT outcome is illustrated by the recent study by McCarroll et al (2009) showing that deletion of the entire UGT2B17 gene determining a numer of HLA gene alleles can result in an alloimmune response associated with aGvHD. This multi-center study (1345 patients) initially examined six common deletions (UGT2B17, UGT2B28, GSTT1, GSTM1, LCE3C and OR51A2) in a phase I discovery study using 414 HLA MRD transplants. The association of the UGT2B17 deletion with acute GVHD was validated in two additional cohorts of, resp., 336 and 595 HLA-identical sibling transplants. Risk of acute GVHD proved to be greater (OR=2.5) when donor and recipient were mismatched for homozygous deletion of UGT2B17.
Moreover, the KIR genetic region encodes variant receptors on NK cells, this cluster contains up to 15 genes, whose al-leles can be identified by a variety of PCR methods. Acceptable genotyping must include typing for the known activating (2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1) and inhibitory KIR genes (2DL1, 2DL2, 2DL3, 2DL5, 3DL1), in addition to the framework genes (3DL3, 2DL4, 3DL2). Now the KIR genes are subject to an in-depth biological association studies (Petersdorf et al., 2013).
In addition, a number of genes (mostly enzymes, and molecule transporters) control pharmacological effects of specific medications used for cytostatic chemotherapy and HSCT, e.g., during conditioning phase, and post-transplant (alkyl-ating drugs, immunosuppressor agents, antibacterial antibiotics etc.). Common polymorphisms of these genes may alter biotransformation or drug transfer across cell membrane in liver (upon oral administration), other organs, or blood cell precursors, thus determining actual pharmacokinetics and individual dose effects of these drugs (Franca et al., 2015).
Some clinically relevant gene variants are located in gene promoter or other regulatory regions of the gene. Such high or low-producing alleles (indel mutations) simply change specific mRNA production levels, without altering specific protein structure. Meanwhile, nucleotide substitution in coding region of the gene may cause gain or loss of specific
protein function (e.g., enzyme activity). Mutational shift of reading frame in coding region may cause loss of gene function or deficient production of intact protein in the cell.
Hence, minimal nucleotide differences in numerous functional genes may cause sufficient deviations of cell damage and recovery after HSCT. These polymorphic alleles could increase or diminish biological action of different enzymes, receptors, transporters, transcription factors etc. Therefore, distinct polymorphic gene alleles exhibiting high-or low-producing activities may be associated with major complications of HSCT and survival in HSC recipients.
Hence, even single functional gene polymorphisms may significantly influence the donor-recipient interplay and cause distinct risks for HSCT outcomes. Therefore, the aim of our comparative review was to summarize effects of some functional gene alleles of donor and recipient upon drug toxicity, incidence and severity of aGvHD and other tissue-specific complications post-transplant.
Cytotoxic drug pharmacokinetics and GvHD depend on recipient genes
Conditioning treatment with cytostatic drugs causes profound damage of mucosal epithelium (oral and intestinal mucositis), vascular endothelium (veno-occlusive hepatic disease), urothelium (hemorrhagic cystitis). Incidence and severity of these early complications, in particular, aGVHD, seem to depend on genetically altered transmembrane transport or biotransformation transformation (activation or conjugation) of busulfan, cyclophosphamide, and other cytotoxic drugs. A number of studies concerning genetic associations between pharmacokinetic parameters and GVHD occurrence were discussed by Franca et al. (2015). The workers reviewed several studies in pediatric transplantation and concluded that only few gene variants detected in HSC recipients could affect drug pharmacokinetics, e.g., ABCB1 (pGp) gene for in vivo MTx concentrations; CYP3A upon CsA and Tacrolimus pharmacokinetics in plasma, whereas GST-A1, GST-P were associated with changed kinetics of oral Busul-fan. Among a number of pharmacogenes, only genetic tests for CYP3A seemed to be recommended for wide clinical application in the patients undergoing chemotherapy. However, low- and high-producing variants of numerous genes and, especially, gene constellations may be determined pre-trans-plant, in order to adjust individual dosage of cytotoxic drugs and immune suppressors.
Our search in literature performed for different HSCT settings has also shown a clear dependence between drug transporter gene variants of a well-known methylene tetrahy-drofolate reductase (MTHFR) polymorphism, and clinical GVHD post-transplant (Table 1). These modifying effects depended, mainly, on gene variants in recipients, except of an SLC19A1 gene variant (a folate transporter) in donor cells. Interestingly, Murphy et al. (2012) have shown a correlation between high-producer 677CC MTHFR in donor and GvHD severity. Meanwhile, SNPs of dihydrofolate reductase (DHFR) and solute carrier (SLC19A1) genes (both related to folate metabolism) in donors were associated with reduced risk of aGvHD, as shown by Laverdiere et al. (2015). Hence, one may suggest that folate synthesis and its pharmacokinet-ics may depend on both recipient and donor gene variants.
Table 1. Reported effects of pharmacologically relevant gene variants upon aGVHD incidence
Gene, alleles Clinical groups Clinical parameters Associations Reference
20 genes related to methotrexate and cyclosporine metabolism 420 HLA-matched allo-HSCT recipient-donor pairs aGVHD (stage 3-4), cGVHD Recipient genes ABCC1 (rs8058040), ABCC2 (rs3740065), ATIC (rs2177735) are predictive for grade III-IV aGVHD. Donor dihydrofolate reductase and SLC19A1 (folate transporter) SNPs - reduced risk of severe acute GvHD Laverdière et al., 2015
MTHFR SNPs, 677C>T and 1298A>C 140 allo-HSCT patients and donors 5-year survival, aGvHD, and 9 other outcomes Donor MTHFR 677CC genotype was associated with earlier GVHD (P = .003), and more severe acute GVHD (P = 0.02). Murphy et al., 2012
MTHFR SNPs, 677C>T 107 patients and donors with leukemia receiving HSCT Oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and VOD of the liver, aGvHD grade, TRM and survival Recipient MTHFR polymorphisms (C677T) were associated with acute GvHD Rocha et al., 2009
677TT genotype in MTHFR gene MTHFR genotypes in 159 recipients and their donors aGVHD Association between 677TT genotype in recipient and a lower incidence of grade I-IV acute GVHD Sugimoto K. et al., 2008
IMPDH1 SNPs IVS8-106 G>A (IMPDH=target enzyme for mycophe-nolate mofetil) 240 allo-HSCT recipients and donors aGvHD grade IVS8-106 G/G genotype in recipients correlates with higher aGVHD risk Cao et al., 2012
SNPs in ERalpha and ERbeta genes 108 patients receiving a bone marrow transplant from an HLA-matched sibling donor aGVHD, overall survival (OS) Recipient polymorphism for PvuII-XbaI RFLP of ERalpha (intron 1): occurrence of acute GVHD and lower OS Middleton et al., 2003
Laverdiere et al. (2015), when studying 420 recipient-donor pairs, have performed deep DNA sequencing of 20 candidate genes related to MTx and CsA metabolism and GvHD occurrence. Of them, only few genetic variants were significantly associated with acute GvHD risk. In particular, the risk was associated with genetic variations in recipients related to pharmacodynamic pathways of methotrexate and cyclosporine A, including methylenetetrahydrofolate reduc-tase (MTHFR) rs2274976 and rs3737967, and 5-aminoimi-dazole-4-carboxamide ribonucleotide formyltransferase/ inosine monophosphate cyclohydrolase (ATIC, rs17514110) proved to be risk alleles (see Table 1). Similarly, donor SNPs in NFATC2 (molecular target of cyclosporine A) increased risk of worse prognosis. Meanwhile, single nucleotide polymorphisms of dihydrofolate reductase (DHFR) and solute
carrier (SLC19A1) genes of donors (both related to folate metabolism) were associated with reduced risk of aGvHD.
Different types of clinical outcomes and appropriate phar-macogene correlations were also studied by Rocha et al. (2015). In 107 donor-recipient pairs, the authors studied allelic frequencies of the following genes: P450 cytochrome (CYP2B6), glutathione-S-transferase family (GST), multi-drug-resistance gene (MDR gene), methylenetetrahydro-folate reductase (MTHFR) and vitamin D receptor (VDR). The endpoints, along with acute GvHD, were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), transplantation-related mortality (TRM) and survival. Most effects of pharmacologically relevant recipient gene CYP2B6 (cyclophosphamide metabol-
Effects of donor gene SNPs upon immune response in acute GvHD:
Acute GVHD is primarily caused by alloreactive donor lymphocytes which expand and migrate to the target tissues, mainly, skin and intestinal epithelium. aGVHD is an allo-ag-gressive inflammatory process triggered and regulated by multiple cytokines, and chemokines produced both by the host and donor cells. These gene variants may express high-and low-producing activity thus modifying clinical course of aGVHD. These interactions are far from clearness, and are subject to many gene association studies.
Most factors studied in connection with GVHD risk are produced by innate immune cells (macrophages, neutrophils, natural killers etc.). To search effects of donor and recipient gene variants upon GVHD, we performed a selection of appropriate genetic associations in available literature (PubMed, keywords: GVHD, gene polymorphism). Included were the studies with positive associations found, where both recipients and their donors were genotyped. We asked whether donor, or host hyperactive genes (or both) are associated with aGvHD as the most life-threatening immune complication of allo-HSCT. The results are summarized in Table 2.
Table 2. Distinct effects of recipient and donor gene variants upon aGVHD
Gene, alleles Clinical groups Clinical parameters Associations Reference
GvHD enhanced
TNFA-1031 (T>C), -863 (C>A), -857 (C>T), -238 (G>A), TNFB+252 (A>G) and TNFRII codon 196 (T>G) 138 unrelated donor/recipient pairs underwent allo-HSCT aGVHD incidence and severity TNFA-857 C/C genotype in donors and TNFB+252 G allele-positive recipients associated with the development of grades II-IV aGVHD. Xiao et al., 2011
IL-2 gene promoter, -330 T>G SNP 95 consecutive donor and recipient pairs aGVHD incidence At least one IL-2 G allele in recipient of: twofold increased risk of acute GVHD. MacMillan et al., 2003
Inflammation genes: 259 SNPs in 53 genes 268 allo-HSCT patients and donors with steroid-resistant aGVHD and Severe aGVHD (GIT affection) Donor genotypes: IFNG (rs2069727) and IL6 (rs1800797) suggest higher HVHD risk Alam et al., 2015
IL-6 -174 G>C polymorphism Seven cohort studies, (1287 recipient and donor pairs) aGVHD risk and severity Donors with IL-6 G allele: more frequent grade I-IV aGVHD and grade II-IV aGVHD Choi et al., 2012
Meta-analysis (n=41) and own data on 16 informative SNPs linked to aGVHD 1424 matched donor-recipient pairs after allo-HSCT (MAC), patient and donor SNPs genotyped or imputed aGVHD stages associated with SNPs IL6 rs1800795 in donor were associated with higher risk for moderate/severe aGVHD; Chien et al. (2012)
ic modification) were connected with acute therapy effects (oral mucositis, hemorrhagic cystitis). Recipient VDR TaqI showed correlations with TRM and overall survival. SNPs in estrogen receptor genes may also modify response to steroid hormone therapy. A study by Middleton (2003) has shown that an estrogen receptor alpha SNP (PvuII-XbaI) in recipient may affect both GvHD incidence and survival rates. All these association studies on SNPs and HSCT outcomes should be, however, reproduced in further works, oriented for search for appropriate candidate genes.
Despite certain evidence of associations between polymorphisms in genes encoding metabolizing enzymes (CYP3A4/3A5, UGT1A9) or drug transporters (ABCB1, ABCC2, SLCO1B1) and pharmacokinetics of several im-munosuppressive drugs, diagnostic genotyping in order to calculate optimal initial dose for the patient is uncommon in clinical practice, probably due to absence of proof that clinical outcome is really improved when such genotyping was performed for the drug dosage. To the present time, clinical recommendations in relation to pharmacogenetic biomark-ers exist only for CYP3A5 testing, in order to determine initial tacrolimus dose in patients (Pikard et al., 2016).
Gene, alleles Clinical groups Clinical parameters Associations Reference
ILlß +354 allele 58 consecutive allo-HSCT recipients and their donors GVHD, IL1ß in blood and saliva Association between aGVHD, donor IL1ß genotype, and high IL-1ß levels in saliva Resende et al., 2013
IL-7Ra: rs1494555 and rs1494558 SNPs 590 recipient/ donor pairs HLA-MUD HCT GVHD and TRM Donor SNPs: IL-7Ra: rs1494555GG and rs1494558TT are associated with aGvHD and cGvHD. Shamim et al., 2013
SNPs in 13 cytokine genes .... Patients and donors aGVHD Donor SNPs: IL-4Ra and IL-12, Recipient IL-1a -889/C allele showed significant association with aGVHD Noori-Daloii et al., 2013
IL-17 rs2275913 197A SNP 438 pairs of patients and their unrelated donors aGvHD, IL-17 secretion by T cells Donor IL-17 197A allele associated with a higher risk of aGVHD Espinoza et al. (2011)
IL-10 -1082 G > A, -819 C > T, -592 C > A SNPs 11 studies with 3588 recipients and 3221 donors aGvHD risk and severity Donors with an IL-10 -819 CC genotype: more frequent grade I-IV aGVHD; recipients with IL-10 -592 CC higher risk for grade II-IV aGVHD Cho et al., 2015
Meta-analysis (n=41) and own data on 16 informative SNPs linked to aGVHD 1424 matched donor-recipient pairs after allo-HSCT (MAC), patient and donor SNPs genotyped or imputed aGVHD stages associated with SNPs IL10 SNPs (rs1800871 and rs1800872) in recipient associated with decreased aGVHD risk Chien et al. (2012)
IL-10 and IL-10Rbeta gene SNPs 309 HLA-identical sibling donor and recipient pairs aGVHD, cGVHD Difference in IL-10 genotypes between patient and donor combined with recipient IL-10Rbeta A/A genotype predisposed to acute GvHD, and protected against chronic GvHD Sivula et al., 2009
38 SNPs in 19 immuno-regulatory genes Pediatric HSCT setting aGVHD severity Three donor SNPs: IL10-1082GG, and TLR4-3612TT with aGVHD: grade III-IV, donor IL10-1082GG, and Fas-670CC + CT, recipient IL18-607 TT + TG genotypes: association with aGvHD grades II-IV Masetti et al., 2015
NOD2 polymorphisms: 3 SNPs 464 recipient-donor pairs, ATG-treated Risk of infections and severe aGVHD Donor NOD2 SNP8 constitutes a risk factor of severe aGVHD Jaskula et al., 2014
NOD2/CARD15 SNPs 342 unrelated transplants: recipients+ donors aGvHD risk, overall survival Donor NOD2 SNP13 is a risk factor for GvHD III/IV and survival Holler et al., 2008
TLR9 (T1237C; T1486C), IL23R (A1142G), and NOD2 SNP8 (R702W), SNP12 (G908R) and SNP13 (1007fs) 142 AML patients after non-T-cell-depleted myeloablative allo-HSCT from HLA-matched sibling donors Overall survival, 5-year mortality, aGVHD Recipients with NOD2 gene variants: higher risk for acute GVHD grade III-IV Elmaagacli et al., 2011
Gene, alleles Clinical groups Clinical parameters Associations Reference
Codons 10 and 25 of TGFB1 427 myeloabla-tive-conditioned transplanted patients aGVHD, NRM, overall survival Recipient's genotype of TGFB1:grades II-IV associated with increased aGVHD Berro et al., 2010.
TGF-betal codon 25 G/C polymorphism (rs:1800471) 86 patients after BMT from HLA-matched siblings aGVHD Recipients with the TGF-GG genotype: severe aGVHD significantly more common than with CC or GC set Rashidi-Nezhad et al., 2010
CTLA-4 SNPs 312 donor-recipient pairs aGVHD, regimen toxicity Recipient CT60G>A[GG] genotype, were independent aGvHD risk factors Karabon L et al, 2015
3 CTLA-4 gene polymorphisms 72 thalassemia patients and their unrelated donors aGVHD and other outcomes Recipient association and CT60-AA, and onset of grade II-IV and grade III—IV aGVHD. Recipient association: for the 88-bp allele of the CTLA-4 (AT)n SNP Orrù S et al., 2012
CTLA-4 alleles and haplotypes for the -318C>T and the 49A>G SNPs 112 patients and their sibling donors in allo-HSCT (Tunis) Chronic GVHD Donor CTLA-4 -318C49G haplotype may be a significant risk factor for developing chronic GVHD Sellami et al., 2011
SNPs in MORC4, CD14, TLR4, NOD2, SLC22A4, SLC22A5, CARD8, NLRP3, and CLDN2 .... Donors, recipients, allo-HSCT Overall survival, aGVHD, Recipient allele CD14 (rs2569190): associated with aGVHD Norén et al., 2016
SNPs in CD28, inducible co-stimulator, CTLA4, granzyme B, Fas and Fas ligand 240 pairs of recipients and donors MUD GVHD, survival, relapse risk Unrelated donors with granzyme B +55 genotype (AA): a risk factor for grades II-IV aGVHD Xiao et al., 2012
MMP-1 -1607 SNP 111 donors and recipients aGVHD risk Donor MMP 2G/2G: associated with aGVHD stage I-IV Chukhlovin et al., 2003
MADCAM1 rs2302217 AA genotype 87 HLA-matched allo-HSCT recipients and their donors aGVHD, cGVHD occurence Recipients with MADCAM1 rs2302217 AA homozygosity had more common aGVHD and cGVHD Ambruzova et al., 2009.
VDR Apal, TaqI and Fokl alleles 123 Polish recipients and their donors aGVYD risk, death risk Two donor SNPs ApaI AA and FokI FF significantly contributed to grade II-IV aGVHD Bogunia-Kubik et al., 2008
GvHD-protective alleles
IL-10 and IL-10Rbeta gene SNPs 309 HLA-identical sibling donor and recipient pairs aGVHD, cGVHD Difference in genotypic IL-10 between patient and donor combined with recipient IL-10Rbeta A/A genotype protected against chronic GvHD Sivula et al., 2009
IL-10 promoter -1082, -819 and -592, their haplotypes 57 pediatric allo-HSCTs (MAC), both recipients and donors aGvHD, TRM, OS Recipients with IL-10 promoter GCC haplotypes showed lower risk of severe aGVHD and TRM Goussetis et al., 2011
IL-10 promoter gene SNPs PubMed and Embase databases and 10 studies aGVHD Positive correlation between the -592AA homozygote and -1082A allele in recipient: lower risk of severe aGvHD in HSCT Zhu et al., 2013
Gene, alleles Clinical groups Clinical parameters Associations Reference
SNPs in IL-1beta, IL-1-receptor antagonist, IL-6, IL10, and TNF alpha 993 transplant recipients and their HLA-identi-cal sibling donors aGVHD Recipient IL10 -592A/A genotype was associated with a decreased risk of grade III or IV acute GVHD
13 cytokine genes .... Recipients and donors aGVHD Negative association was found between aGVHD and donor IL-10/GCC haplotype, or donor IL-4RaA allele Noori-Daloii, et al., 2013
FOXP3, <15 (GT) repeats in promoter region 252 allo-matched HSCT, and their donors aGvHD, grade III-IV Lower incidence of aGVHD in cases of donors with <15 (GT) repeats in FOXP3 Noriega et al., 2015
TGF-beta1 codon 10 TT, TC and CC genotypes 168 subjects Iranian HLA-matched sibling BMT: donor/ recipient pairs aGVHD incidence and severity Recipients with the T allele developed aGVHD significantly less than those without the T allele Noori-Daloii et al., 2007
TLR9 (T1237C; T1486C), IL23R (A1142G), and NOD2 SNP8 (R702W), SNP12 (G908R) and SNP13 (1007fs) 142 AML patients after non-T-cell-depleted myeloablative allo-HSCT from HLA-matched sibling donors Overall survival, 5-year mortality, aGVHD Donor gene variant of IL23R was much less in severe aGVHD grade III-IV Elmaagacli et al., 2011
IL-23R (1142A>G) and BPI (A645G) genes 304 patients and their donors aGVHD, OS, risk of relapse Two donor SNPs: IL-23R and BPI alleles associated with less severe aGVHD Wermke et al., 2010
1142 G>A SNP in the IL-23 receptor gene (IL23R) and 3 SNPs in the NOD2/CARD15 gene 231 children after allo-HSCT and their donors aGVHD incidence and severity Reduced incidence of aGVHD grade II-IV in patients transplanted from a donor with the IL23R SNP Gruhn et al., 2009
Fcy receptor type IIIA (FCGR3A) (rs396991) 99 allo-HSCT recipients with myeloid malignancies, and their unrelated donors TRM, OS, aGVHD, cGVHD Recipient 158V genotype associated with a reduced risk of cGVHD and a trend towards a reduced risk of grade II-IV acute GVHD Takami et al., 2011
SNPs in CD28, inducible co-stimulator, CTLA4, granzyme B, Fas and Fas ligand 240 pairs of recipients and donors GVHD, survival, relapse risk Donor CTLA4 gene CT60 variant allele (AA genotype) had a reduced incidence of grades II-IV acute GVHD Xiao et al., 2012
CXCL12 gene polymorphism (rs1801157) 323 patients and donors Toxicity, aGVHD, viral reactivation aGvHD (grades I-IV) lower in recipients with CXCL12-3' A allele or AA homozygous genotype Bogunia-Kubik et al., 2015
One may conclude from these data that functional gene polymorphisms of immune factors/receptors associated with incidence/severity of GvHD are most commonly by donor origin. Recipient gene alleles are connected with aGVHD in few association studies. Therefore, donor cells seem mostly determine genetic background in clinical aGVHD.
A similar gene association data with GvHD reported by 2012 were statistically evaluated by Chien et al. (2012). Their
own results obtained by Affymetrix arrays (genome-wide sequencing) of 1298 allogeneic transplants (both donor and patient samples) were tested to confirm previously reported candidate genes predisposing for GvHD. Of 40 previously reported candidate SNPs, 6 were successfully genotyped by the authors, and 10 other traits were added (imputed) and passed statistical criteria, thus getting association data from >40 studies on different polymorphic candidate genes able to influence aGvHD incidence.
To assess relative importance of candidate genes, the authors (Chien et al., 2012) used an algorithm involving minimal allele frequency (MAF) and Hardy-Weinberg equilibrium parameters, in order to assess reliability and contribution of the given allele to GvHD occurrence. Among the tested alleles, they have selected IL-10 promoter alleles (IL10 SNPs rs1800871 and rs1800872); IL-6 promoter variant rs1800795; IL2 allele (rs2069762); rs3087243 in CTLA4, rs4364254 in HPSE, and rs1801131 in MTHFR genes. In general, the tested gene set largely corresponds to the list of informative genes revealed in our analysis (see Table 2). As a result, the rs1800795 SNP in IL6 donor genotype was associated with sufficiently increased risk for grade III-IV aGVHD following HSCT.
Surprisingly, Chien et al. (2012) have revealed very low replication rate for the candidate gene SNPs, i.e., only 7%. Such low replication rates are encountered in early genetic literature and may result from non-standardized techniques of SNP detection, or application of formal statistical criteria.
Another class of non-MHC genes affecting HCT outcome is illustrated by the recent study by McCarroll et al. (2009) showing that deletion of the entire UGT2B17 gene determining a numer of HLA gene alleles can result in an alloimmune response associated with aGvHD. This multi-center study (1345 patients) initially examined six common deletions (UGT2B17, UGT2B28, GSTT1, GSTM1, LCE3C and OR51A2) in a phase I discovery study using 414 HLA MRD transplants. The association of the UGT2B17 deletion with acute GVHD was validated in two additional cohorts of, resp., 336 and 595 HLA-identical sibling transplants. Risk of acute GVHD proved to be greater (OR=2.5) when donor and recipient were mismatched for homozygous deletion of UGT2B17.
Thrombosis risk and gene polymorphism
In the world literature some early data were published regarding probable risk of thrombotic complications post-HSCT (McDonald GB et al., 1993).
Later on, a single-center study by Tunisian authors concerned incidence of central venous catheter (CVC)-related thrombosis in HSCT recipients (Abdelkefi et al., 2005). The laboratory prothrombotic markers included factor V Leiden, the prothrombin gene Gly20210A mutation, plasma an-tithrombin levels, and protein C and S activity. A total of 171 patients were included. Of them five (2.9%) and three (1.7%) patients had evidence of protein C and protein S deficiency, respectively. Only one patient had an antithrombin deficiency (0.6%). In total, 10 patients (5.8%) were heterozygous for the factor V Leiden mutation, and one patient had heterozygous prothrombin G20210A mutation (0.6%). Thrombosis was diagnosed in four out of 20 patients (20%) with a inherited prothrombotic abnormality compared to nine of 151 patients (6%) who did not have a thrombophilic marker (relative risk 3.3 CI 95% 1.1-9.9). These results provided a marginal evidence of inherited prothrombotic abnormalities contributing to CVC-related thrombosis in HSCT group.
Over last 2 decades, studying posttransplant effects of functional thrombophylic variants have not yielded some distinct results. E.g., a work by Azik et al. (2015) concerned patients possible correlations between venous thromboembolism (VTE) in 92 pediatric allo-HSCT patients within 100 days post-transplant. The studied prothrombotic risk factors included factor V Leiden, prothrombin G20210A, methylene-tetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations; and serum homocysteine and lipopro-tein(a), plasma antithrombin III, protein C, and protein S levels in all patients pre-transplant. Eight patients (9%) proved to be heterozygous for factor V Leiden, 5 (6%) were homozygous for MTHFR 677TT, 12 (14%) were homozy-gous for MTHFR 1298CC, and 2 (2%) were heterozygous for prothrombin G20210A polymorphism. VTE was diagnosed in 5 patients (5.4%); a prothrombotic risk variant been found in 3 of them. In summary, no significant relationship between VTE and inherited prothrombotic risk factors. Hence, an inherited prothrombotic risk for VTE after HSCT is low, but should be considered.
Effects upon survival rates
General effects of different-level gene polymorphisms upon transplant-related mortality (TRM) were recently performed by Sucheston-Campbell et al. (2015). Of course, better matching for HLA combined with supportive care and infection prophylaxis have improved survival over the past two decades. Hovewer, numerous SNP variants may lead to differential gene transcription, translation, and protein structure. These changes have the potential to modify immune responses or side effects of chemotherapy and/or radiation, and thus, survival outcomes in HCT patients.
Of those, genetic associations of NOD2/CARD15 with survival after HCT draw special attention. However, the first encouraging results was not confirmed in next studies. E.g., the largest NOD2/CARD15 study to date, 567 donor-recipient pairs both HLA matched and mismatched with primary diagnoses including hematologic malignancies, non-hemato-logic malignancies, and nonmalignant diseases, found only a borderline association (p=0.049) of a recipient SNP with increased TRM and conflicting results in the non-malignant patient groups (Kreyenberg, 2011). Some effect upon patients survival was revealed, and weak statistical correlation was found exclusively for recipient-side (SNP13) associated with increased pTRM (<0.01).
As referred in abovementioned review by Sucheston-Camp-bell et al. (2015), many works concerned candidate genes have been tested for informative SNP associatiated with transplant-related mortality(TRM) and overall survival (OS), checking SNPs in oxidative genes (GSTM1, UGT2B17), cy-tokine and chemokine genes, their receptors in both donors and recipients. Numerous studies beared on receptor-mediated immune recognition (FCGR3A, CTLA4 ), and NOD2/ CARD15, like as VDR, MTHFR etc. So far, the candidate gene studies are at phase of association studies, without current clinical applications, due to their limited reproducibility.
Discussion
Since several decades, recipient/donor HLA matching was a sine qua non condition for optimal HSCT. Transplantation of cord blood cells and HSC from haploidentical donors has changed this paradigm. By opposite, minor differences in HLA patterns are now regarded as a sufficient factor of graft-versus-leukemia effect in the patient. Moreover, HLA allelic loss (segmental chromosome 6 deletions) in leukemia clones is considered a factor of erroneous HLA typing, immune escape of tumor cells and higher relapse risk after HSCT (Taborelli et al., 2006; Dubois et al., 2012).
Moreover, a number of other functional gene variants may affect survival and risk of complications following in HSCT patients and are grouped as follows:
1. Most by recipient origin: drug metabolism-controlling genes (pharmacogenes) influencing biotransformation, time-dose kinetics and effects of cytotoxic drugs used in conditioning therapy are mostly genes expressed mostly in recipient liver, spleen and and target cells (both normal and malignant)
2. Mostly donor cell genes: cytokine genes encoding inter-leukins and some key inflammation regulators - mostly donor genes
3. Both recipient and donor origin: receptor and contact protein genes which encode innate receptors recognizing bacterial antigens and contacts proteins.
Key role of activated cytokine network in aGvHD genesis is widely recognized. The cytokine response seems to be switched by severe damage to normal tissues caused by conditioning therapy. At this time point, the relatively resistant innate immune cells, such as monocyte/macrophages, produce a series of inflammatory cytokines, i.e., IL-1, IL-4, IL-6, IL-12, IFNy, TNFa etc. The aseptic inflammation is further enhanced by antigens from exogenous microbiota invading due to loss of epithelial integrity (Fig. 1, from Ramadan, Paczesny, 2015). The authors suggest specific induction of IL-6, IL-4, and IL-12 of, respectively, Tc17/Th17, Tc2/Th2, and Tc1/Th1 lymphocyte populations. Those, together with NK cells and monocytes/macrophages, exert cytolytic effects upon target epithelial tissues causing classical acute GvHD. We see here that the candidate genes well fit the general chain of cytokine/receptor switching in evolving inflammatory reaction underlying aGVHD.
Medical applications of these protein factors as potential therapeutic targets are confirmed by clinical trials with appropriate anticytokine monoclonal antibodies are, mostly, at Phase I/II, and their clinical significance is not yet fully assessed. Other cytokine antagonists should be tested for their efficiency to prevent aGvHD, e.g., monoclonal antibodies against gamma chains of the main cytokines. In rodent models, pharmacological blockade of TNF-a, IL-6, and C-C chemokine receptor type 5 (CCR5) is proven to prevent aGvHD development (Teshima et al., 2016).
Figure 1. Pathogenesis of acute GVHD. Pre-transplant conditioning causes tissue damage. The affected tissues and cells release DAMPs (HMGB-1), PAMPs (LPS) from gut microbiota as well as inflammatory cytokines (e.g., IL-ip, IL-6, and TNF-a) contributing to the "cytokine storm." These are the first danger signals that activate host APCs, which activate and polarized donor T-cells toward pathogenic T-cells (TH1 and TH17 for CD4 and TCI, TC17 for CD8). Activated pathogenic T-cells infiltrate target organs (i.e., GI tract, liver, skin) and amplify local tissue destruction. The presence of regulatory T-cells (Tregs) helps to reduce GVHD severity (Ramadan, Paczesny, 2015).
As seen from current studies, intestinal damage in severe GvHD forms is caused by donor T cells which attack intestinal stem cell (ISCs) niches. The antigen-presenting cells stimulated by foreign (mismatched) HLA (minor and minor ones) enhance these events by secreting IL-1, IL-6, TNF and other inflammatory cytokines. The affected mucosal layers allow bacterial dysbiosis and invasion of intestinal microflora, thus enhancing acute inflammatory reactions (Teshima et al., 2016).
Among T cell modulators, CTLA-4 and PD-1 are now intensively studied as a possible target for immune checkpoint inhibitors (e.c., ipilimumab). The CTLA-4 (CD152) is expressed both on CD4 and CD8 T cells, being, e.g., an inhibitor of autoreactive T cell populations (Buchbinder, Desai, 2016). Therefore, its functional alleles were studied by several groups for their GVHD risk (see table 2). In most studies, the recipient CTLA-4 alleles, hence, surviving lymphoid cells (may be, in thymus - Buchbinder), seem to increase AGVHD risk.
The immune stimulation from intestinal microbiota is mediated by the s.c. pattern-recognizing receptors known as TLR4 and NOD receptors in mammals (Heidegger et al., 2014). Therefore, their genetic variants may also play a significant role in GvHD modification, as seen from some studies (see Table 1).
From these literature data concerning a number of polymorphic functional genes we readily see that, in most cases, aG-VHD is associated with donor functional polymorphisms, as seen from Table 2.
Biological significance of donor-associated gene factors may be interpreted in terms of their cell sources and specific effects on target immune cell populations. E.g., interfer-on-gamma is ubiquitously produced by activated T lymphocytes, NK cells, macrophages, epithelial cells.
E.g., IL-1beta is known to be synthesized by monocytes, macrophages, neutrophils, whereas proinflammatory IL-6 is produced by monocytes, macrophages and T cells. IL23 is again secreted by monocytes and dendritic cells, like as anti-inflammatory, immunosuppressive cytokine IL10 synthesized by monocytes, T4+ and B cells. Hence, most cytokines informative for gene polymorphism and associated with aGVHD, are produced by monocytes/macrophages. The donor monocytes are renewed from the GM-CFUs within 1st month posttransplant and settle in different tissues, transforming to macrophages in addition to residual recipient macrophages. Therefore, both recipient and donor gene variants may function early after transplant thus determining their effects on certain cytokine synthesis and GVHD development. At later terms, however, donor macrophage populations seem to prevail among resident macrophages, due to natural replacement processes. The dynamics of this process is worth of further studies.
Contact and attraction molecules
Cell adhesion and attraction molecules may be also involved into pathogenesis of posttransplant complications. E.g., Thyagarajan et al. (2013) has tested SNPs of some contact
molecules (ICAM1, PECAM and SELL) in 425 recipient-donor pairs subjected to allogeneic HSCT, aiming to assess their effects upon clinical outcomes (TRM, GVHD). The rs5498 in the ICAM1 in both recipients and donors associated with a lower risk of Transplant-related mortality, however, without effect upon GVHD rates and severity.
Chemokines attracting distinct cell polulations to the inflammation site, could be also functionally polymorphic. A study by Bogunia-Kubik (2015) concerned CXCL12 (SDF-1) gene polymorphism (rs1801157) in 323 patients/donors with evaluation of total toxicity, aGVHD, and viral reactivation. Presence of the CXCL12-3' A gene variant was associated with lower grade of aGVHD, thus suggesting altered migration of hematopoietic cells to the target organs.
Moreover, migration of alloreactive cells in extracellular matrix depends on local activity of collagen-degrading enzymes (matrix metalloproteinases, MMP's).
Interestingly, in our previous studies in 111 recipient/donor pairs we have found that the more transcriptionally active allele an MMP-1 gene (-1607 2G) harbored by donor HSC is associated with more frequent aGVHD in allo-HSCT patients whereas more active MMP-1 allele in recipient reduces aGvHD frequency (Chukhlovin et al., 2003). Severe GvHD (grade II-IV) was not detected with donors negative for MMP1 2G, whereas being rather common when donors carried a 2G allele of MMP1 (0/16 versus 13/44, p=0.014), as seen in Fig. 2.
14
12
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10 y
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fli
3 x> o
6 .E
a
>
2 <
AGVHD grade
Figure 2. Increased incidence of acute GvHD in alloge-neic hematopoietic transplants from donors carrying a hyperproducing MMP1 2G allele (Chukhlovin et al., 2003).
Some gene variants participating acting at cell and tissue barriers may alter basic tissue functions. For instance, one may suggest prothrombotic effects of PAI1-1 4G variant in veno-occlusive disease post HSCT, or MMP1 2G polymorphism to higher ECM permeability and easier migration of alloreactive donor lymphocytes to the target epithelium, etc. (Fig. 3).
Figure 3. Suggested biological effects of donor hyperactive gene variants leading to major HSCT complications.
Hence, one may suggest that active functional alleles of non-HLA genes, if present in donor cells, seem to dominate and may play a sufficient role in alloaggressive effects of donor cytotoxic T cells, thus causing severe aGVHD forms.
From Fig. 4, one may see that the local host cells (APCs) are releasing proinflammatory cytokines (TNF, IL-1, IL-6), being stimulated by damage products from cytotoxic treatment. Special affection is inflicted to intestinal wall. Death of intestinal epithelium brings about higher permeability to microbes and microbial toxins which are recognized by the NOD2 and toll-like receptors (TLRs) on the resident APCs . Their role in other complications (veno-occlusive disease, severe mucositis needs further studies.
Figure 4. Schematic overview of gut bacteria-mediated initiation of acute graft-versus-host disease (Heidegger et al., 2014).
During the toxic conditioning regimen with total-body irradiation and/or chemotherapy, the destruction of intestinal epithelial cells leads to the loss of the epithelial barrier function. Similar effects occur at skin and other epithelial borders. Activated host and/or donor antigen-presenting
cells prime allo-reactive donor T cells, which promote acute GVHD (Heidegger et al., 2014).
Most of these cytokine genes are showing informative associations showing a role of donor cells in GVHD. We cannot, of course, perform an additional donor selection for these gene variants. However, we may consider numerous non-HLA gene polymorphisms as risk factors, first of all, for AGVHD, and modify the scheduled GVHD prophylaxis regimens.
Appropriate multiplex prediction models are now developed and gradually tested, in order to personalize post-transplant preventive treatment. For example, multiple findings on donor- and recipient functional gene variants allowed of designing certain informative SNP panels for donors and recipients (Kim et al., 2012). The authors tested a group of recipients' SNPs of IL2, IL6R, FAS, EDN1, TGFB1, and NFKBIA, and donor polymorphisms of NOS1, IL1B, TGFB2, NOD2/CARD15, TNFRII, IL1R1, and FCGR2A. This selection was based on a previous big study in a total of 259 SNPs in 53 genes in 394 pairs of donors and recipients. The resulting computed risk models provided predictive stratification of the patients into low-risk (Q1), moderate-risk (Q2, Q3), and high-risk (Q4) groups with regard of OS, RFS, nonre-lapse mortality (P=0.0043), and acute GVHD (P<0.0001).
Conclusion
Extensive studies are needed in order to specify distinct candidate genes for prediction of adverse pharmacological effects of cytostatic drugs in hematopoietic stem cell transplantation, covering large donor and recipient populations of various ethnicities, patient age, and different modes of he-matopoietic stem cell transplants.
Modifying effects of functional gene polymorphisms, e.g., those influencing production of cytokines, adhesion and recognition molecules, are associated with incidence and severity of aGVHD. Less is known about associations of gene polymorphisms with other HSCT complications (mucositis, VOD etc.).
We have revealed some predominance in donor SNPs of immune-controlling genes associated with acute graft-versus-host disease, as seen from the results of several comparative studies. This should be taken into account when planning haploidentical transplants and infusions of donor lymphoid cells in immunotherapy of tumors. For example, one may expect more expressed graft-versus-leukemia effect from the donor T cells exhibiting more active gene alleles (e.c., IL-6, IL-7R, MMP-1 et al.). By contrary, these protein products may be targeted by specific inhibitors to prevent excessive aGVHD.
Knowledge on the functional gene variants in donor may be applied for planning distinct schemes of cellular immune therapy, e.g., haploidentical HSCT, donor lymphocyte infusions, other cases of suggested graft-versus leukemia (lymphoma) effect.
Conflict of interest
No conflict of interests is declared.
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Помимо HLA-системы: риск иммунных осложнений аллотрансплантации гемопоэтических стволовых клеток зависит от функциональных не-HLA аллелей донорского происхождения
Алексей Б. Чухловин
НИИ детской онкологии, гематологии трансплантологии им. Р. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Россия
Резюме
Эта обзорная статья касается генетической предрасположенности к ряду тяжелых иммунных осложнений при аллогенной трансплантации гемопо-этических стволовых клеток (алло-ТГСК), которые зависят в основном от различий донора и реципиента по набору системы ИЬА и так называемым минорным факторам совместимости, например -определенным аллелям ИЬА-О и другим белкам иммунной системы (ТОТ-а, 1Ь1-р, 1Ь-2, -6, 10) и их рецепторам, что связано с общей выживаемостью, возможным отторжением трансплантата или острой реакцией «трансплантат против хозяина» (оРТПХ). Кроме того, ТГСК является сложной процедурой с применением множества цитотоксических агентов, применяемых при кондиционирующей терапии, а также иммуносупрессивных препаратов, используемых после ТГСК. Минимальные различия в нукле-отидных последовательностях ряда функционально активных генов могут вызвать значительные различия в уровнях повреждения клеток и их восстановления после ТГСК. Эти полиморфные аллели могут повысить или снизить биологическое действие различных энзимов, рецепторов, молекул-транспортеров, факторов транскрипции ДНК и т.д. Поэтому конкретные полиморфные генные аллели, проявляющие высокую или низкую активность, могут быть ассоциированы с основными осложнениями ТГСК и выживаемостью реципиентов. Имеющиеся данные о многочисленных эффектах полиморфизмов не-ИЬА-генов в парах «донор-реципиент» позволил
нам сделать следующие выводы: 1) функционально активные гены, контролирующие метаболизм препаратов, используемых при кондиционирующей терапии, были, в основном, генами реципиента, которые экспрессируются, главным образом, в печени, селезенке и кроветворных клетках-мишенях химиотерапии; 2) наибольший интерес представило преобладание эффекта генов донорского происхождения, ассоциированных с оРТПХ, по сравнению с малым влиянием аналогичных аллелей реципиентов ТГСК.
Это преимущество эффектов донорских аллелей следует принимать во внимание при планировании гаплоидентичных трансплантаций и инфузий лим-фоидных клеток донора при иммунотерапии злокачественных новообразований. Например, можно ожидать большей экспрессии эффекта «трансплантат против лейкоза» при введении донорских Т-кле-ток, несущих более активные аллели ряда генов (например, 1Ь-6, 1Ь-7К., ММР-1 и др.). Напротив, эти белки могут быть мишенью соответствующих тар-гетных препаратов с целью предотвращения тяжелых форм оРТПХ.
Ключевые слова
Трансплантация гемопоэтических клеток, исходы, функциональные полиморфизмы генов, иммунные осложнения, фармакокинетика.
