Some cytokines are believed to play a role in the development of acute and chronic GVHD after allo-hematopoietic stem cell transplantation. It has been reported that TNF-α and IL-10 gene polymorphisms are associated with the production of those cytokines and the development of graft failure after organ transplantation and systemic lupus erythematosus. We examined whether TNF-α and IL-10 gene polymorphisms affect the severity of acute GVHD (aGVHD) and chronic GVHD (cGVHD). Sixty-two and 54 patients were available for the analysis of aGVHD and cGVHD, respectively. We analyzed the gene polymorphisms derived from pre- and post-transplant blood cells. Donor-derived TNF2 allele (A) was more frequently detected in patients with aGVHD III/IV than those aGVHD 0-II (2/6 vs 2/56) (P = 0.04). The donors of the patients with cGVHD more frequently possessed a greater number of alleles (allele 13 or more which contain 26 or more CA repeats) in IL-10.G than those without (13/26 vs 5/28) (P = 0.02), and the patients with cGVHD had more CA repeats in donor-derived IL-10.G than those without (mean = 25.2 vs 23.4) (P= 0.01). Donor-derived TNF-308 and IL-10.G alleles may contribute to severe aGVHD and cGVHD, respectively, and will help us distinguish those patients at high risk for GVHD. Bone Marrow Transplantation (2000) 26, 1317–1323.
GVHD is an important complication that influences morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the role of donor T cell activation in the induction of GVHD has been confirmed, there is evidence to suggest that several cytokines are also involved.1
In the development of acute GVHD (aGVHD), it is likely that cytokines released as a result of conditioning regimen toxicity and infection initiate the synthesis of other cytokines, which amplify target organ injury. Tumor necrosis factor-α (TNF-α) is one cytokine known to play a major role in the early phase of aGVHD.123 TNF-α is produced mainly by monocytes, or by T and B cells, and has proinflammatory activity.4 It can activate endothelial cells and induce the expression of cell adhesion molecules, which are associated with leukocyte homing.5 Moreover, it evokes expression of HLA molecules, which activate antigen specific T cells. It has been reported that the maximal level of TNF-α in serum is related to the severity of aGVHD and elevated levels during pre-transplant conditioning are associated with aGVHD.67 There have been reports that TNF-α is also related to the development of chronic GVHD (cGVHD).89
The clinical features of cGVHD are similar to those of several autoimmune diseases, and can include autoantibody formation.10111213 IL-10 was originally defined as a cytokine able to alter the balance of mouse Th1 and Th2 activity. IL-10 is produced by a variety of cells, including monocytes, B cells and T cells. IL-10 can also function as a negative regulator of TNF.13 Llorente and colleagues14 reported that in some autoimmune diseases, spontaneous production of IL-10 was upregulated and production of autoantibody was IL-10 dependent in patients with systemic lupus erythematosus (SLE).15
Recently, cytokine gene polymorphisms associated with the production of those cytokines have been identified. There is a single base polymorphism in TNF at position-308 (G/A).16 The rare allele TNF2 (A) has been reported to be closely associated with HLA A1, B8, and DR317 and, in individuals with the TNF2 allele, the production of TNF-α is markedly increased, caused by high transcriptional activation.18 At IL-10 position −1082, a single base polymorphism (A/G) in the IL-10 promoter region, positivity of allele A is associated with low IL-10 production.19 It has been reported that post-heart transplant patients with A at IL-10–1082 (low IL-10) and with TNF2 (high TNF-α) were susceptible to graft rejection.20 Furthermore, IL-10.G, a microsatellite polymorphic region at −1064 of the IL-10 promoter,21 was suggested to play a role in the development of SLE since the distribution of the IL-10.G allele differed between SLE patients and healthy controls.22
Such reports prompted us to investigate whether the gene polymorphisms of TNF-α and IL-10 are associated with the incidence of either severe aGVHD or cGVHD. We examined TNF-α and IL-10 gene polymorphisms of allo-HSCT patients using pre- and post-transplant blood cells, and investigated the association between such polymorphisms and the incidence of severe aGVHD or cGVHD.
Materials and methods
We analyzed 62 patients (aged from 13 to 48 years old) who received non-T cell-depleted allo-HSCT at our institute or an associated hospital and for whom genomic DNA was obtained from blood cells after engraftment. The patients were tested for TNF-α and IL-10 gene polymorphisms after engraftment. The replacement of a patient's blood cells with the donor-derived ones after HSCT was confirmed by the analysis of short tandem repeat polymorphisms. Fifty-seven of the 62 patients were also tested for the gene polymorphisms before transplantation, which are considered to be of recipient origin. Forty-six patients were transplanted with cells from an HLA fully matched related donor, three with cells from an HLA 1 locus mismatched related donor, and 13 with cells from a serologically HLA-A, B, and DR matched unrelated donor. Peripheral blood stem cells (PBSC) of the donor were grafted in five cases (three patients were PBSC + bone marrow and two were PBSC). Underlying diseases were acute leukemia (AL; n = 32), chronic myelogenous leukemia (CML; n = 21), myelodysplastic syndrome (MDS; n = 5), and severe aplastic anemia (SAA; n = 4).
TBI as pre-transplant conditioning
Pre-transplant conditioning regimens were based on primary diseases. Basic regimens were administration of cytarabine, etoposide, and TBI (12 Gy) for AL, busulfan, cyclophosphamide, and TBI (3 Gy) for CML, cyclophosphamide and TBI (12 Gy) for MDS, and cyclophosphamide and total lymph node irradiation (7.5 Gy) for SAA. Some regimens were tailored to the individual, due to the disease condition. Five patients received more than 12 Gy of TBI. The other 57 patients received 12 Gy or less.
GVHD prophylaxis and treatment
For GVHD prophylaxis, 52 patients received cyclosporin A (CsA) combined with short-term methotrexate (st-MTX) and 10 received CsA alone. When aGVHD grade II or more was diagnosed, intravenous prednisolone or methyl-prednisolone was administered.
Evaluation of GVHD
aGVHD was diagnosed and graded based on previously published criteria.23 cGVHD was clinically diagnosed if the patient exhibited typical features of cGVHD,11 and in 12 such cases, the diagnosis was ascertained histologically.
Detection of allele of TNF-α and IL-10 gene polymorphism
Genomic DNA was extracted from buffy coat cells or mononuclear cells collected from bone marrow or peripheral blood using SepaGene DNA extraction kit (San-ai, Tokyo, Japan). Polymerase chain reactions (PCR) were performed in a volume of 50 μl containing 100 ng of genomic DNA, 2 μM of each primer, 200 μM of dNTP, 1.5 mM of MgCl2, 10 mM of Tris-HCl (pH 8.3), 50 mM of KCl, and 1 U of Taq polymerase (Takara, Tokyo, Japan). PCR parameters were 94°C for 3 min, followed by 35 cycles of 94°C for 1 min, 62°C for 1 min and 72°C for 1 min, and a final extension of 5 min at 72°C for analysis of TNF-308. For analysis of IL-10.G, they were 94°C for 3 min, followed by 30 cycles of 94°C for 1 min and 70°C for 2 min, and a final extension of 5 min at 70°C. The following primer sequences were used: For TNF-308: sense: 5′-AGGCAATAGGTTTTGAGGGCCA T-3′, and antisense: 5′-TCCTCCCTGCTCCGATTCCG-3′.16 For IL-10.G: sense: 5′-CCCAACTGGCTCCCC TTACCTT-3′, and antisense: 5′-CATGGAGGCTGGATAGGAGGTC-3′. As the TNF position −308 single base polymorphism (G/A) is detectable by NcoI restriction of the amplified PCR product, the TNF1 allele gives two fragments of 87 bp and 20 bp and the TNF2 allele a single 107 bp fragment,16 the PCR products were digested with NcoI (New England Biolabs, MA, USA) and analyzed on a 12% polyacrylamide gel. The amplified product of IL-10.G was denatured and electrophoresed at 60 watts on 6% polyacrylamide urea gel at 50°C and subjected to silver staining. To determine the IL-10.G allele, PCR products of some samples with a homozygous genotype were sequenced in both directions with an ABI PRISM Dye Terminator Cycle Sequencing Kit (Perkin-Elmer, Foster City, CA, USA), the same primer used for PCR, and an ABI 310 DNA automated sequencer (Perkin Elmer). The sequenced samples were used as size markers for electrophoresis. The allele number was assigned according to a previous report.21 For example, alleles 9, 10, and 13 were identical to having 22, 23, and 26 CA repeats in the gene, respectively.
Patients who died in the early phase after HSCT were excluded from the analysis on cGVHD. χ2 test or Fisher exact test was used for the statistical analysis of the association between each factor and the incidence of severe aGVHD (grades III/IV) and cGVHD. The Student's t-test was used for comparison of the mean number of CA repeats for the longer IL-10.G allele between patients with and without cGVHD. Multivariate analyses including any factors showing significance or a trend to correlation to GVHD (P < 0.1) were performed with logistic regression model.
Incidence of acute and chronic GVHD
aGVHD developed in 39 (62.9%) of 62 patients. Grade II or more severe aGVHD developed in 17 patients (27.4%), and grade III or IV aGVHD in six patients (9.7%). We required more than 100 days after transplantation to evaluate for cGVHD. Eight patients were excluded from the analysis on cGVHD. Four patients died of aGVHD grade IV, one died of early relapse, one died of sepsis, one committed suicide 3 months after HSCT, and one patient exhibited symptoms similar to cGVHD but was not diagnosed with cGVHD. Twenty-six (48.1%) of 54 patients analyzed in the present study developed cGVHD. We obtained post-engraftment blood cells from all the evaluated patients to analyze donor-derived cytokine gene polymorphisms. Fifty-seven pre-transplant samples of 62 cases evaluated for aGVHD, and 50 pre-transplant samples of 54 cases evaluated for cGVHD were available for the analyses of the recipient-derived cytokine gene polymorphisms.
Patient age, donor source, HLA identity, use of PBSC, TBI dose and GVHD prophylaxis
Age was not significantly higher in the patients with grade III or IV aGVHD (aGVHD III/IV) than grade II or less (aGVHD 0–II) nor different between patients with and without cGVHD. The mean age of patients with aGVHD 0–II and III/IV was 28.0 and 33.2 years old, respectively (P = 0.23). That of patients with and without cGVHD was 28.7 and 27.5 years old, respectively (P = 0.67). The differences between related donor and unrelated donor, and between HLA full match and 1 locus mismatch, were not associated with the incidence of aGVHD III/IV (P = 0.33 and P > 0.99, respectively) and cGVHD (P = 0.75 and P > 0.99, respectively). Immune female donor to a male recipient showed correlation to neither aGVHD III/IV nor cGVHD (P = 0.10 and 0.32, respectively). Use of PBSC as a donor source, TBI at more than 12 Gy as pre-transplant conditioning, and methods for GVHD prophylaxis were also not associated significantly with the incidence. Two of five patients grafted with PBSC and four of 57 patients grafted without PBSC developed aGVHD III/IV (χ2 = 5.72; f = 1, P = 0.069). One of four patients grafted with PBSC and 25 of 50 patients grafted without PBSC developed cGVHD (χ2 = 0.93; f = 1, P = 0.61). Two of five patients who received more than 12 Gy and four of 57 patients who received 12 Gy or less developed aGVHD III/IV (χ2 = 5.72; f = 1, P = 0.069). Three of four patients receiving more than 12 Gy and 23 of 50 patients receiving 12 Gy or less developed cGVHD (χ2 = 1.25; f = 1, P = 0.34). Two of 10 patients receiving CsA alone, and four of 52 patients receiving CsA and st-MTX for GVHD prophylaxis developed aGVHD III/IV (χ2 = 1.453; f = 1, P = 0.25). Seven of nine patients receiving CsA alone and 19 of 45 patients receiving CsA and MTX developed cGVHD (χ2 = 3.80; f = 1, P = 0.072) (Table 1). In this study aGVHD grade II or more did not show significant relationship to development of cGVHD (9/13 in aGVHD II or more and 17/41 in aGVHD 0 or I; χ2 = 3.05; f = 1, P = 0.11).
In pre-transplant samples, the TNF2 (A) allele was detected in five cases, four of whom also possessed the TNF2 allele in post-engraftment samples. The four patients whose pre- and post-transplant samples possessed TNF2 were grafted from HLA-identical siblings. The other patient was grafted from an HLA full matched relative, her mother. All the genomes with TNF2 allele were heterozygous (TNF1/2) and did not possess HLA A1, B8, and DR3 haplotype which is known to be associated with TNF2.17 Although the TNF2 allele from pre-transplant blood cells was not associated with severity of aGVHD, that from post-engraftment blood cells was. In an analysis of pre-transplant samples, three of 51 patients with aGVHD 0–II and two of six patients with aGVHD III/IV possessed TNF2 (χ2 = 5.06; f = 1, P = 0.081). In an analysis of post-engraftment samples, two of 56 patients with aGVHD 0–II and two of six patients with aGVHD III/IV possessed TNF2 (χ2 = 7.95; f = 1, P = 0.043) (Table 2). The TNF2 allele from either pre- or post-engraftment samples was not associated with the incidence of cGVHD. In an analysis of pre-transplant samples, three of 24 patients with and none of 26 patients without cGVHD possessed TNF2 (χ2 = 3.46; f = 1, P = 0.10). In an analysis of post-engraftment samples, two of 26 patients with and none of 28 patients without cGVHD possessed TNF2 (χ2 = 2.24; f = 1, P = 0.23) (Table 2).
Fifteen of 57 pre-transplant samples possessed allele 13 or more, which contain 26 or more CA repeats.21 Twenty-one of 62 post-engraftment samples possessed allele 13 or more. Regardless of allele number, IL-10.G, from either pre- or post-engraftment samples, was not associated with severity of aGVHD. In an analysis of pre-transplant samples, 14 of 51 patients with aGVHD 0–II and one of six patients with aGVHD III/IV possessed allele 13 or more (χ2 = 0.32; f = 1, P > 0.99; Table 2). In an analysis of post-engraftment samples, 18 of 56 patients with aGVHD 0–II and three of six patients with aGVHD III/IV possessed allele 13 or more (χ2 = 0.77; f = 1, P = 0.40; Table 2). The allele number of IL-10.G from pre-transplant samples was not associated with the incidence of cGVHD, but that from post-engraftment samples was. In an analysis of the former, nine of 24 patients with and four of 26 patients without cGVHD possessed allele 13 or more (χ2 = 3.17; f = 1, P = 0.11; Table 2). In an analysis of the latter, 13 of 26 patients with and five of 28 patients without cGVHD possessed allele 13 or more (χ2 = 6.27; f = 1, P = 0.020; Table 2 and Figure 1). In post-engraftment samples, mean CA repeats numbered significantly more in the group with cGVHD than without cGVHD. In pre-transplant blood cells, the difference was not significant. The repeats numbered 25.2 in post-engraftment samples of patients with cGVHD and 23.4 in those without cGVHD (P = 0.013; Figure 2). They numbered 24.1 in pre-transplant samples of the patients with cGVHD and 23.4 in those without cGVHD (P = 0.27).
Multivariate analyses of risk factors for GVHD
Multivariate analyses were performed using a logistic regression model in order to prove that donor-derived TNF2 and IL-10.G alleles are independent risk factors for severe aGVHD and cGVHD, respectively. TNF or IL-10 gene alleles and other factors showing a tendency to correlate to GVHD (P < 0.1) were included in the analyses.
Donor-derived TNF2, use of PBSC, and high dose TBI (>12 Gy) were included in the analysis of risk factors for aGVHD III/IV. Although the number of patients suffering aGVHD grades III/IV were very small (only six patients), in this model, all these factors showed significant association with aGVHD III/IV as follows. Donor-derived TNF2: odds ratio (OR) = 29.4; confidence interval (CI), 1.7–531.7; P = 0.021, PBSC: OR = 34.5; CI, 2.4–510.4; P = 0.009, TBI >12 Gy: OR = 19.6; CI, 1.2–321.1; P = 0.038 (Table 3, upper left). This result indicates that donor-derived TNF2 is a significant and independent risk factor, as well as PBSC and high-dose TBI for severe aGVHD. Furthermore, in another logistic regression model including recipient-derived TNF2, PBSC and high-dose TBI, recipient-derived TNF2 was also identified as a significant risk factor for aGVHD as follows. Recipient-derived TNF2: OR = 18.5; CI, 1.2–290.0; P = 0.037, PBSC: OR = 32.3; CI, 2.2–473.0; P = 0.012, TBI >12 Gy: OR = 18.5; CI, 1.2–290.0; P = 0.037 (Table 3, lower left).
Donor-derived IL-10.G allele (⩾13) and CsA alone for GVHD prophylaxis were included in the analysis for risk factors for cGVHD. In this model, only donor-derived IL-10.G allele showed significance as follows. IL-10.G allele ⩾13: OR = 4.5; CI, 1.3–16.1; P = 0.020, CsA alone for GVHD prophylaxis: OR = 4.7; CI, 0.8–26.8; P = 0.086 (Table 4, left). Therefore, IL-10.G allele ⩾13 is expected to be a strong risk factor for developing cGVHD.
Next, analyses limited to sibling-transplant cases were performed in the same way. For severe aGVHD, donor-derived TNF2 allele (OR = 21.3; CI, 1.2–365.0; P = 0.036) and PBSC (OR = 35.7; CI, 2.1–600.4; P = 0.013) were identified as significant risk factors with the logistic regression model including donor-derived TNF2, PBSC, and high dose TBI (Table 3, upper right). However, in another model including recipient-derived TNF2, PBSC, and high dose TBI, only PBSC (OR = 23.3, CI, 1.6–356.6, P = 0.022) was identified as a significant risk factor, while, recipient-derived TNF2 (OR = 14.3; CI, 0.9–215.2; P = 0.055) and high-dose TBI (the same value as TNF2) were not (Table 3, lower right). In the case of cGVDH, no significant risk factors were identified but donor-derived IL-10.G allele ⩾13 (OR = 3.9; CI, 0.9–17.7; P = 0.076) and CsA alone for GVHD prophylaxis (OR = 5.6; CI, 0.9–34.3; P = 0.062) showed tendencies to correlate to cGVHD (Table 4, right).
GVHD is still a frequent complication of allo-HSCT. Severe aGVHD is known to be fatal and cGVHD to affect quality of life. About 6% of the patients developed fatal aGVHD and 48% cGVHD in this series. To improve the prognosis and quality of life of patients receiving allo-HSCT, it is important to lessen the incidence of severe aGVHD and cGVHD. The etiology of and high risk factors associated with GVHD need to be elucidated if high-risk patients in need of a more intensive prophylaxis are to be identified. Although several cytokines, including TNF-α and IL-10, are believed to be important to the development of GVHD,123 prediction for dysregulated production of these cytokines before HSCT seems to be impossible. Recently, TNF and IL-10 gene polymorphisms associated with cytokine production,1819 the development of SLE,22 and graft rejection after heart transplantation20 have been reported. If such polymorphisms are associated with the incidence of GVHD, one may be able to identify those patients at high-risk for GVHD.
In the present study, the TNF2 allele, which contributes to the up-regulation of TNF-α production,18 was expected to correlate to severe aGVHD. Especially, that of donor-origin was identified as a significant and independent risk factor not only in all of this series but also in limited cases of sibling transplant. However, that of recipient-origin was not a significant risk factor in sibling transplant cases. The TNF gene lies within the HLA locus.17 Therefore, when an allo-HSCT donor is an HLA-identical sibling of the patient, the genotype of TNF is also often identical. In our study, all of the patients whose donors had TNF2, had TNF2 themselves before allo-HSCT. In addition, the number of individuals with TNF2 was small in our series (only six patients developed aGVHD III/IV). Therefore, our results do not necessarily indicate that the TNF from donor-derived, not recipient-derived cells, is associated with severe aGVHD. As there is a close association between the serum TNF-α level during pre-transplant conditioning and aGVHD,67 we presume that TNF2 of recipient-origin is associated with severe aGVHD. However, in cases where aGVHD developed relatively late after engraftment, the TNF-α released from the donor-derived cells may play more important roles in the development of aGVHD. Any conclusion must await a study containing a larger number of unrelated HSCT cases. TNF2 is possibly a risk factor for development of severe aGVHD. However, some patients with donor or self TNF2 will not develop severe GVHD. In our series, two of five patients associated with TNF2 did not develop aGVHD grade II or more. In these patients, other factors such as IL-10, increased production of which is associated with fewer transplant-related complications,24 may overcome the high transcriptional activation capacity. TNF2 was not associated with HLA A1, B8, and DR3, unlike in another study17 and the allele frequency of TNF2 (0.037, nine of 238 alleles in this study) was much smaller than values reported for Caucasians (0.16–0.19).162025 This difference may be due to a difference of race, and partly explain the lower frequency of aGVHD in Japanese than in Western populations.2627 In this series, also, severe aGVHD occurred less frequently than has been reported in Western countries.2829
Having more CA repeats within the IL-10.G in cells of donor-origin was associated with the development of cGVHD. The multivariate analysis of risk factors for cGVHD intended for all cases in this series disclosed that allele 13 or more in the IL-10.G was the only significant and independent risk factor for cGVHD. Although no significant factors were identified in the limited cases of sibling transplant, donor-derived IL-10.G allele exhibited a trend to correlate to cGVHD as well as CsA alone for GVHD prophylaxis. This is the first report of an association between cGVHD and IL-10.G polymorphism, moreover, that in donor-derived cells. IL-10 is an immune and inflammatory regulator produced by Th2, which suppresses production of Th1 cytokines.30 It was observed in a murine cGVHD model that production of Th2 cytokines was enhanced and Th1 cytokines impaired, suggesting that activation of Th2 cells is responsible for autoantibody formation and immunosuppression in cGVHD.31 However, Körholz et al32 reported a significant decrease in IL-10 production by mononuclear cells activated in vitro in cGVHD patients. It is not clear whether this discrepancy is due to a different pathogenesis of human cGVHD and murine cGVHD, or to a difference in the method of testing serum samples or samples from cells activated in vitro. In some autoimmune diseases, it has been reported that IL-10 production is upregulated.14 In human cGVHD, the clinical features are often similar to those of autoimmune diseases and autoantibody formation is sometimes observed.10111213 Therefore, we speculate that IL-10.G affects IL-10 production and is one of the factors responsible for autoimmune disease-like manifestations.
A recent study on the association between aGVHD and cytokine gene polymorphisms using genomes from recipient-derived cells showed an association of TNFd3 and smaller allele number of IL-10.G with aGVHD.25 We could not confirm the contribution of IL-10.G to aGVHD, but it is worth noting that our study also showed that IL-10.G from donor-derived cells contributes to cGVHD. Thus, we speculate that IL-10 released from engrafted blood cells is involved in the pathogenesis of cGVHD.
In summary, donor- or recipient-derived TNF −308 and donor-derived IL-10.G may contribute to the development of severe aGVHD and cGVHD, respectively. The difference in the cytokine gene polymorphism associated with each GVHD type may reflect differences in the pathogenesis and the clinical features of each type. We propose that TNF-α is one of the factors responsible for aGVHD, and IL-10, for cGVHD. It is hoped that these polymorphisms will help us distinguish those patients at high-risk for GVHD before HSCT so that a more intensive prophylaxis can be administered.
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The authors thank Mrs M Sakaue for technical assistance.
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Cite this article
Takahashi, H., Furukawa, T., Hashimoto, S. et al. Contribution of TNF-α and IL-10 gene polymorphisms to graft-versus-host disease following allo-hematopoietic stem cell transplantation. Bone Marrow Transplant 26, 1317–1323 (2000). https://doi.org/10.1038/sj.bmt.1702724
- cytokine gene polymorphism
- allogeneic HSCT
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