Significance of CTLA-4 and CD14 Genetic Polymorphisms in Clinical

LETTER TO THE EDITOR Signiﬁcance of CTLA-4 and CD14 genetic polymorphisms in clinical outcome after allogeneic stem cell transplantation

Bone Marrow Transplantation (2007) 40, 1001–1002; CTLA-4 were analyzed, employing the same methodology doi:10.1038/sj.bmt.1705850; published online 10 September 2007 as Perez-Garcia et al.5 We found no significant association of either CTLA-4 polymorphism with overall survival (HR for the GG and AG genotypes was 0.90 (95% confidence In addition to the genes involved in the ‘HLA barrier’ in interval (CI): 0.77–2.34) as compared with HR 0.95 (95% solid organ and hematopoietic stem cell transplantation CI 0.65–5.18) for the AA genotype). Furthermore, neither (HSCT), and to the polymorphisms of the KIR family CTLA-4 polymorphisms influenced disease recurrence. genes of natural killer cell receptors, there has been growing On the other hand, we found that donor AA genotype at attention in the past few years regarding the role of other rs3087243 predicted for both grade III–IV acute and gene polymorphisms of molecules potentially involved in extensive chronic GVHD by multivariate analysis that immune reactions following HSCT.1 In particular, atten- included common potential influential factors (Table 1). tion has been paid to the sequence polymorphisms Finally, we found no correlation between rs231775 haplo- of cytokine and cytokine gene receptor genes, as these types and acute or chronic GVHD occurrence (not shown). molecules are involved in the modulation of host response These data are similar to those reported by Perez-Garcia to tissue injury and inflammation, with the ensuing et al.5, in terms of the association between the rs3087243 activation of donor competent cells2 (for arecent extensive genotype and GVHD, whereas they differ regarding the review, please refer to Petersdorf1). Beyond the events influence on survival or disease recurrence. We feel that the linked to the T-cell receptor activation that follows different transplant settings (sibling versus MUD donor), the binding of T cell to HLA molecule–peptide complex, and possibly the smaller number of patients in our study, are the balance between T-cell activation and inactivation is the most obvious explanations for these discrepancies. dependent on a system of antigen-independent signaling Response to host-damaged cells after preparative ther- molecules, the B7(CD80/CD86)/CD28 interaction path- apy and exposure to endogenous bacteria antigens might way. The cytotoxic T-cell CTLA-4 antigen is highly represent the triggering events in GVHD development, as a homologous with regard to CD28, and competes for step in the activation of specific immunity pathways.2 CD14 B7 binding, resulting overall in downregulation of T-cell functions as an innate pattern recognition receptor, and response; thus, CTLA-4 supposedly plays a key role in after binding to lipopolysaccharide, promotes signaling tolerance regulation.3 The association of some CTLA-4 through the toll-like receptor-4 .6 A TT polymorphism gene polymorphisms, possibly causing a reduction of at À159 in the CD14 promoter (rs2569190) has been mRNA and protein levels, with a variety of autoimmune associated with increased CD14 transcriptional activity, disorders, has been previously reported.4 resulting in ahigher density of CD14 on monocyte Recently, Perez-Garcia et al.5 reported that the clinical membrane and enhanced innate immune activation;7 also, outcomes of recipients of HLA-identical allogeneic stem the circulating levels of soluble CD14 are increased.8 cell transplantation from a sibling donor could be predicted Reduced post transplant graft survival following lung by the analysis of CTLA-4 polymorphism. They studied transplantation has been observed in patients with the two common CTLA-4 polymorphisms in 536 HLA- TT genotype.9 Thus, we sought to determine the CD14 identical sibling donors for allogeneic HSCT and found promoter polymorphism in our patient population, em- that the donor CT60 polymorphism reduced overall ploying apreviously described Real-Timemethodology. 10 survival (hazard ratio (HR), 3.80), due to higher incidence We found that recipient TT genotype was associated with a of relapse (HR, 1.71), when at least one G allele was significantly higher-risk of both acute and chronic GVHD present, and increased the development of acute GVHD in multivariate analysis (Table 1), whereas donor genotype (HR, 1.54) in the presence of the AA genotype. showed no correlation with GVHD occurrence. Conver- We wish to report our experience on CTLA-4 genotyping sely, we found no significant association between rs2569190 in the setting of HLA-identical matched unrelated donor polymorphism (either in the donor or the recipient) and the (MUD) transplantation. We studied 147 recipients of a rate of infections, overall survival or incidence of relapse myeloablative MUD transplant and their donors; the (not shown). recipient/donor pairs were matched for HLA A, B and C Thus, the present data add to the growing body of at least at the antigen level, and all were genotyped for information that common allelic variants in promoter regions DRB1 and DQB1 alleles. GVHD prophylaxis included of genes encoding for molecules involved in either the innate methotrexate and cyclosporin A plus antithymocyte (CD14) or adoptive (CTLA-4) immune reactions are globulin. The þ 49AG (rs231775, according to the associated with an increased risk of GVHD after allogeneic National Center for Biotechnology Information dbSNP stem cell transplantation. Prospectively, these molecules nomenclature) and CT60 (rs3087243) polymorphisms in represent potential targets for novel therapeutic interventions. Letter to the Editor 1002 Table 1 Association of CTLA-4 and CD14 polymorphisms with References GVHD after unrelated stem cell transplantation 1 Petersdorf EW, Malkki M. Genetics of risk factors for graft- CTLA-4 (rs3087243) CD14 (rs2569190) versus-host disease. Semin Hematol 2006; 43: 11–23. 2 Ferrara JL, Reddy P. Pathophysiology of graft-versus-host- HR 95% CI, P HR 95% CI, P disease. Semin Hematol 2006; 43: 3–10. Acute GVHD 2.16 1.11–4.03 Po0.001 1.85 1.07–3.29 P ¼ 0.01 3 Snanoudj R, de Preneuf H, Creput H, Arzouk C, Deroure N, Chronic GVHD 1.79 1.06–3.23 Po0.01 1.93 1.25–2.89 Po0.001 Beaudreuil B et al. Costimulation blockade and its possible future use in clinical transplantation. Transpl Int 2007; 19: 693–704. Acute GVHD includes only grade III–IV disease, whereas chronic GVHD, 4 UedaH, Howson JM, Esposito L, HewardJ, Snook H, only extensive disease. CTLA-4 polymorphism refers to the donor AA Chamberlain G et al. Association of the T-cell regulatory gene genotype at CT60; CD14 polymorphism refers to the recipient TT genotype CTLA4 with susceptibility to autoimmune disease. Nature at À159. Hazard ratio (HR) and 95% confidence interval (CI) were 2003; 423: 506–511. calculated using multivariate analysis adjusted for age, donor/recipient 5 Perez-Garcia A, De la Camara R, Roman-Gomez J, Jimenez- cytomegalovirus status, BM or PBSC source and sex mismatch. Velasco A, Encuentra M, Nieto JB et al. CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors. Blood 2007; 110: 461–467. 6 Triantafilou M, Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Acknowledgements Immunol 2002; 23: 301–304. 7 Gregory CD. CD14-dependent clearance of apoptotic cells: This work was supported by grants from MIUR no. relevance to the immune system. Curr Opin Immunol 2000; 12: 2004068284_002 and ADMO, Florence. 27–34. 8 Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, AM Vannucchi1, S Guidi1, P Guglielmelli1, S Glinz1, Martinez FD et al. A polymorphism in the 50 flanking region of L Lombardini1, A Busca2, F Locatelli2, AM Dall’Omo3 the CD14 gene is associated with circulating soluble CD14 and A Bosi1 levels and with total serum immunoglobulin E. Am J Respir 1Department of Hematology, University of Florence, Cell Mol Biol 1999; 20: 976–983. Florence, Italy; 9 Palmer SM, Klimecki W, Yu L, Reinsmoen NL, Snyder LD, 2 Ganous TB et al. Genetic regulation of rejection and survival Bone Marrow Transplant Centre, San Giovanni Battista following human lung transplantation by the innate immune Hospital, Turin, Italy and receptor CD14. Am J Transplant 2007; 7: 693–699. 3 Transplantation Immunology Service, San Giovanni Battista 10 Heesen M, Kunz D, Rossaint R, Blomeke B. Real-time PCR assay Hospital, Turin, Italy with fluorescent hybridization probes for rapid genotyping of the E-mail: amvannucchi@unifi.it CD14 promotor polymorphism. Clin Chem 2000; 46: 1866–1877.

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