Graft-Versus-Host Disease

A single nucleotide polymorphism of IL-17 gene in the recipient is associated with acute GVHD after HLA-matched unrelated BMT

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Abstract

IL-17 has an important role in the host defense against extracellular pathogens and the pathophysiology of autoimmune diseases. This study retrospectively examined the impact of a single-nucleotide polymorphism (rs2275913, G197A) in the IL-17 gene of a total 510 recipients with hematologic malignancies and their unrelated donors on the clinical outcomes in HLA-matched myeloablative (discovery study) and nonmyeloablative (validation study) BMT through the Japan Marrow Donor Program (JMDP). In the discovery study, the presence of a 197A genotype in the recipient resulted in a higher incidence of grades II–IV acute GVHD (hazard ratio (HR), 1.87; 95% confidence interval (CI), 1.23–2.85; P=0.004). The donor IL-17A genotype did not significantly influence the transplant outcomes. The validation study showed a trend toward an association of the recipient 197A genotype with an increased risk of grades III–IV acute GVHD (HR, 5.84; 95% CI, 0.75–45.72; P=0.09), as well as a significantly increased risk for chronic GVHD (HR, 3.86; 95% CI, 1.29–11.59; P=0.02). These results suggest an association of the 197A genotype in the recipient side with the development of acute GVHD.

Introduction

Hematopoietic SCT represents a therapeutic approach that can potentially cure many patients with otherwise fatal hematologic malignancies. However, its utility is limited because of transplant-related life-threatening complications including GVHD, infections and disease relapse.1 Among these, acute GVHD is the main cause of early mortality and morbidity. Although HLA matching represents the major genetic determinant in clinical outcome after allo-SCT, recent evidence suggests that non-HLA immune-associated genes are also implicated.2 Previous investigations have revealed that several single-nucleotide polymorphisms (SNPs), which impact on individual immune response to infections and inflammatory reactions are associated with SCT outcomes including the risk of acute GVHD.3, 4, 5, 6, 7, 8, 9, 10, 11, 12

IL-17, also known as IL-17A, is the hallmark cytokine of a new T-helper subset termed Th17.13, 14, 15, 16 γδT cells, macrophages and neutrophils are sources of IL-17 as well.17, 18 IL-17 receptor (IL-17RA), a ubiquitous type-I membrane glycoprotein, is expressed in particularly high levels in hematopoietic tissues.13, 19, 20 IL-17 has important roles in bridging innate and adaptive immunity, and is involved in the host defense against extracellular pathogens, the pathophysiology of autoimmune diseases, and allograft rejection of solid organs.21, 22, 23, 24, 25, 26, 27, 28, 29 Moreover, several reports have so far shown that Th17 cells and IL-17 has a significant impact on the development of acute GVHD in mouse models.30, 31, 32, 33, 34, 35

Recent reports have shown association of SNPs in the IL-17 gene with autoimmune diseases such as rheumatoid arthritis and ulcerative colitis.36, 37, 38, 39 The promoter SNP of the IL-17 gene, rs2275913 (G197A), was found to be associated with the susceptibility of rheumatoid arthritis in the Norwegian population38 as well as that of ulcerative colitis in the Japanese population.36 The finding that GVHD mimics some aspects of autoimmune diseases prompted us to investigate the impact of donor and recipient SNPs in the IL-17 gene (rs2275913, G197A) on the clinical outcomes in patients following allogeneic myeloablative BMT using an HLA allele-matched unrelated donor. The data herein show that the presence of the 197A allele in the recipient is associated with a significantly higher incidence of acute GVHD.

Design and methods

Patients

In a total 510 recipients with hematologic malignancies and their unrelated donors on whom IL-17 genotyping was performed, 360 recipients in the discovery study cohort received myeloablative transplantation between January 1993 and July 2002, and 150 recipients in the validation study cohort received nonmyeloablative transplantation between January 1996 and December 2007. Transplantation was undertaken through the Japan Marrow Donor Program (JMDP) with T-cell-replete marrow from an HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 allele-matched donor. HLA genotypes of patient and donor were determined by the Luminex microbead method described previously (Luminex 100 System; Luminex, Austin, TX, USA).40, 41 Although the Luminex microbead method does not provide unambiguous HLA four-digit typing for all genotypes, JMDP has confirmed that this method can identify all HLA alleles with >0.1% frequency among the Japanese population.42 No patients had a history of any previous transplantation. The final clinical survey of these patients was completed by November 1, 2008. Diagnoses were acute myeloid leukemia in 156 (31%), acute lymphoblastic leukemia in 100 (20%), chronic myeloid leukemia in 94 (18%), myelodysplastic syndrome in 79 (15%), malignant lymphoma in 71 (14%), and multiple myeloma in 10 (2%; Table 1). The recipients were defined as having standard risk disease if acute myeloid leukemia and acute lymphoblastic leukemia were in first CR, malignant lymphoma was in any CR and chronic myeloid leukemia was in any chronic phase and myelodysplastic syndrome. All others were designated as high-risk disease. The myeloid malignancies include acute myeloid leukemia, chronic myeloid leukemia and myelodysplastic syndrome, and the lymphoid malignancies included acute lymphoblastic leukemia and malignant lymphoma. CYA- or tacrolimus-based regimens were used in all patients for GVHD prophylaxis and anti-T-cell therapy such as anti-thymocyte globulin and ex vivo T-cell depletion was not. All patients and donors gave their written informed consent to participate in molecular studies of this nature according to the declaration of Helsinki at the time of transplantation. The project was approved by the Institutional Review Board of Kanazawa University Graduate School of Medicine and JMDP.

Table 1 Donor and recipient characteristics

IL-17 G197A genotyping

Genotyping of IL-17 was performed using the TaqMan-Allelic discrimination method43 with a 7900-HT Real-Time PCR system (Applied Biosystems, Foster City, CA, USA) and results were analyzed using the Allelic Discrimination software program (Applied Biosystems). The genotyping assay was conducted in 96-well PCR plates. The amplification reaction contained template DNA, TaqMan universal master mix and the specific probe rs2275913 designed for SNP of IL-17 G197A (product No. C_15879983_10; Applied Biosystems).

Data management and statistic analysis

Data were collected by the JMDP using a standardized report form. Follow-up reports were submitted at 100 days, 1 year and annually after transplantation. Pretransplant CMV serostatus was routinely tested for only patients but not for their donors. Engraftment was confirmed by an ANC of more than 0.5 × 109/L for at least 3 consecutive days. Acute- and chronic GVHD were diagnosed and graded using established criteria.44, 45 The OS was defined as the number of days from transplantation to death from any cause. Disease relapse was defined as the number of days from transplantation to disease relapse. Transplant-related mortality was defined as death without relapse. Any patients who were alive at the last-follow-up date were censored. The data on causative microbes of infections and postmortem changes in cause of death, as well as the data on supportive care including infections prophylaxis and therapy of GVHD, which were given on institution basis, were not available in this cohort. The analysis was performed using the Excel 2007 (Microsoft Corp, Redmond, WA, USA), OriginPro version 8.0J (Lightstone Inc., Tokyo, Japan) and R (The R Foundation for Statistical Computing, Perugia, Italy) software programs.46 The probability of OS was calculated using the Kaplan–Meier method and compared using the log-rank test. The probabilities of transplant-related mortality, disease relapse, acute GVHD, chronic GVHD and each cause of death were compared using the Grey test47 and analyzed using the cumulative incidence analysis,46 considering relapse, death without disease relapse, death without acute GVHD, death without chronic GVHD and death without each cause as respective competing risks. The variables were recipient age at time of transplantation, sex, CMV serostatus before transplantation, disease characteristic (disease type, disease lineage and disease risk at transplantation), donor characteristics (age, sex, sex compatibility and ABO compatibility), transplant characteristics (TBI-containing regimen, tacrolimus vs CYA and total nucleated cell count harvested per recipient weight) and the year of transplant. The median was used as the cutoff point for continuous variables. The χ2-test and Mann–Whitney test were used to compare two groups. The Hardy–Weinberg equilibrium for the IL-17 gene polymorphism was tested using the Haploview program.5 Multivariate Cox models were used to evaluate the hazard ratio (HR) associated with the IL-17 polymorphism. Covariates found to be significant in univariate analyses (P0.20) were included in the models. For both the univariate and multivariate analyses, P-values were two-sided and outcomes were considered to be significant with P0.05.

Results

Discovery study

Frequencies of the IL-17 genotyping

The IL-17 gene polymorphism was analyzed in 360 unrelated BM donor-myeloablative transplant recipient pairs (Table 1). The genotype frequencies of 197A/A, 197A/G and 197G/G were 16, 46 and 38% in recipients and 14, 51 and 36% in donors. These were similar to previous reports38, 48 in Japanese populations (15, 52 and 33%, respectively) and Caucasian populations (13, 48 and 39%, respectively), and were in accord with the Hardy–Weinberg equilibrium (P=0.91).

Transplant outcome according to the IL-17 genotype

The median follow-up duration in the cohort was 90 months among the survivors (range 4–171 months), 102 recipients (28%) had relapsed or progressed and 187 (52%) had died. Three patients (1%) died before engraftment.

The transplant outcomes according to the IL-17 genotype are summarized in Table 2. The presence of the 197A genotype in the recipient was associated with a significantly higher incidence of grades II–IV acute GVHD (37 vs 23%, P=0.004; Figure 1a) as well as a trend toward a higher incidence of grades III–IV acute GVHD (16 vs 10%, P=0.08; Figure 1b), whereas no significant differences between the 197A/A and the 197A/G genotype in the recipient were seen in incidences of grades II–IV (38 vs 34%, P=0.69) and grades III–IV (17 vs 16%, P=0.96) acute GVHD. The 197A genotype on the recipient side showed a tendency to increase a risk of mortality of acute GVHD as a primary cause of death (6 vs 2%, P=0.095). There were no significant differences in the impact of a 197A in the recipient genotype on OS, transplant-related mortality, relapse, chronic GVHD or extensive chronic GVHD (data not shown). The donor genotype showed no significant effects on either of these variables in addition to acute GVHD (Table 2).

Table 2 Univariate analysis of the association of IL-17 genotype with clinical outcomes after transplantation in the discovery study
Figure 1
figure1

Estimated cumulative incidence curves of grades II–IV (a, c) and grades III–IV (b, d) acute GVHD according to the recipient IL-17 genotype in the discovery study (a, b) and the validation study (c, d).

Multivariate analysis

All of the factors found to be significant in univariate analyses were included in the model. The 197A genotype in recipients remained statistically significant in the multivariate analyses for the development of grades II–IV acute GVHD (Table 3). The presence of a 197A genotype in the recipient side resulted in a higher incidence of grades II–IV acute GVHD (HR, 1.87; 95% confidence interval (CI), 1.23 to 2.85; P=0.004) when adjusted for the other factors in the models. In the combined patient group of acute lymphoblastic leukemia and acute myeloid leukemia, this effect was also positive and was close to statistical significance (HR, 1.84; 95% CI, 0.98–3.43; P=0.056).

Table 3 A multivariate analysis of the association of IL-17 genotype with the clinical outcomes after transplantation in the discovery study

Validation study

The characteristics of the patients in the validation study were similar to those of the patients in the discovery study except for conditioning regimen and recipient age (Table 1). The univariate analysis showed a significant association between the recipient 197A genotype and a higher incidence of grades III–IV acute GVHD (15 vs 4%, P=0.04; Figure 1d), whereas no significant difference in the incidence of grades II–IV acute GVHD (33 vs 26%, P=0.37; Figure 1c). In the multivariate analysis, the validation study performed on nonmyeloablative SCT did not confirm the association of recipient 197A with grades II–IV acute GVHD found in the discovery study, although there was a trend toward an association with grades II–IV acute GVHD (HR, 5.84; 95% CI, 0.75–45.72; P=0.09; Table 4). The recipient 197A genotype was associated with a significantly increased risk for chronic GVHD (HR, 3.86; 95% CI, 1.29–11.59; P=0.02), although this association was not found in the discovery study.

Table 4 A multivariate analysis of the association of IL-17 genotype with the clinical outcomes after transplantation in the validation study

Discussion

The discovery study on the basis of myeloablative transplantation showed that the IL-17 197A genotype on the recipient side was associated with a higher risk of grades II–IV acute GVHD after unrelated HLA-matched myeloablative BMT through JMDP. The validation study for nonmyeloablative transplantation revealed a trend toward the association of the recipient 197A genotype with an increased risk of grades III–IV acute GVHD, although its association on grades II–IV acute GVHD was unclear. Of note, the validation study has demonstrated the association between the recipient 197A genotype and the increased incidence of chronic GVHD. This might reflect the association between the recipient 197A genotype and the risk of late acute GVHD,49 considering that late acute GVHD occurs frequently after nonmyeloablative conditioning transplantation50 and that the manifestation of late acute GVHD is usually indistinguishable from chronic GVHD.51 In this study, the diagnosis of chronic GVHD was based on historical criteria,45 and data on chronic GVHD classification according to the new NIH criteria49 were unavailable, thus suggesting that late-onset, prolonged or delayed acute GVHD could have been diagnosed as chronic GVHD. Taken together, it would appear that the validation cohort data is consistent with the discovery cohort data, although additional validation studies are warranted. This is the first report to demonstrate that IL-17 may be involved in the pathophysiology of acute GVHD in humans.

The role of IL-17 in pathogenesis of acute GVHD remains unclear. Several mouse model experiments have revealed that transfer of IL-17-producing cells induced acute GVHD,33, 34, 35 whereas in contrast there is a report31 showing that donor IL-17-producing cells ameliorated acute GVHD. Host DCs are critical in the initiation of acute GVHD,52, 53, 54 leading to a hypothesis that IL-17-producing cells could modify the function of host DCs through unknown mechanisms. Direct interaction between IL-17 and host DCs may be supported by the fact that DCs expressed IL-17 receptors.26 As the IL-17 G197A polymorphism is located in the promoter region of IL-17 gene, it is conceivable that it may exert some roles in the transcriptional regulation of IL-17 secretion. Thus, investigating the influence of the IL-17 G197A polymorphism on the expression of IL-17 may offer useful information on this issue.

The current study did not show an association between the risk of acute GVHD and the IL-17 genotype in the donor side, implying an influence of host IL-17-secreting cells such as Th17 cells might be more important than the influence of donor IL-17-secreting cells on the pathophysiology of acute GVHD. However, it is still unclear how IL-17 secreted from the host IL-17-secreting cells is involved in the development of acute GVHD. Patient serum and lymphocytes may offer useful information on this issue, although these samples were not obtained for our study.

This study showed that the increased risk of acute GVHD associated with the host 197A genotype of IL-17 did not significantly benefit those with transplant-related mortality and OS after BMT. This might result from the low incidence of acute GVHD-related mortality regardless of the host IL-17 genotype in this cohort. Further investigations for patients at higher risk for acute GVHD including PBSC or HLA-mismatched transplant recipients should be warranted to clarify this issue.

The discovery study also indentified higher recipient age, high-risk disease and CMV-positive recipient as significant predictive factors for worse transplant outcomes (Table 3), which is consistent with earlier studies.55, 56, 57 In addition, similar to a previous report,58 higher donor age was associated with the increased risk of grades III–IV acute GVHD, which might result from the replacement of naive T cells by memory T cells with aging.59

This study suggests that genotyping of IL-17 in transplant recipients before transplantation may provide a 197A-positive recipient an opportunity to avoid the risk of acute GVHD by favoring a BM or cord blood, and an HLA-matched graft rather than a PBSC or HLA-mismatched graft. However, single polymorphisms in one cytokine gene are unlikely to determine the majority of acute GVHD. Future development of predictive strategies including multiple sets of genes will be required.

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Acknowledgements

We are indebted to Drs Hiroko Oshima, Masanobu Oshima and Atsushi Hirao, Ms Kayoko Yamada, Mayu Yamada and Yuki Motohashi at Kanazawa University, and Dr Keitaro Matsuo at Aichi Cancer Center Research Institute for their technical assistance. We thank all of the Japan Marrow Donor Program transplant teams who have contributed patients and donors to this study. This study was supported by grants from the Ministry of Health, Labor and Welfare, and the Ministry of Education, Culture, sports and Technology, and Funds from the Mitani Research and Development Assistance Organization (Kanazawa, Japan) and by the Japan Leukemia Research Fund (Tokyo, Japan).

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Correspondence to A Takami.

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Espinoza, J., Takami, A., Onizuka, M. et al. A single nucleotide polymorphism of IL-17 gene in the recipient is associated with acute GVHD after HLA-matched unrelated BMT. Bone Marrow Transplant 46, 1455–1463 (2011) doi:10.1038/bmt.2010.325

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Keywords

  • IL-17
  • unrelated donor
  • single-nucleotide polymorphism

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