Abstract
Abstract 2010
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been widely carried out as a therapy for several hematological malignances and non malignant disorders.
Graft–versus -host disease is one of the major complications after allo-HSCT with main cause of morbidity and mortality. Donor T lymphocytes play the crucial role in alloimmune recognition and their ability to detect non –self antigens can lead to aGvHD.
The effective recognition and activation of naïve T-cells requires two independent signals. The first, an antigen-specific signal, is sent via the T-cell receptor (TCR) on T-cells. The second signal, termed co-stimulation, is critical for allowing full activation, sustaining cell proliferation, preventing anergy and/or apoptosis, inducing differentiation to effector cells. CD28 is the primary T-cell co-stimulatory molecule. Cytotoxic T-cell antigen (CTLA-4) is a homologous molecule of CD28 which plays an inhibitory role in the early and late stages of T-cell activation. CTLA-4 ligation provides a negative signal for regulation of the cell cycle and inhibits the activity of the transcriptional factors: nuclear factor-kB (NF-kB), nuclear factor of activated T-cells (NF-AT), and activator protein 1 (AP-1). Moreover, CTLA-4 binds to CD28 ligands (CD80 and CD86) with higher affinity and avidity and in that way also inhibits T-cell activation. Since co-stimulatory and down regulatory molecules synthesis depend on the rate of gene transcription and/or translation, polymorphisms in the corresponding genes might result in abnormal expression, function as well as dysregulated trafficking of these molecules within cellular compartments. The human CTLA-4 gene is located on 2q33 which is susceptibility region for autoimmune diseases.
The aim of this study is to investigate the associations between polymorphisms in CTLA-4 gene: CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g6230G>A (CT60, rs3087243), CTLA-4g.10223G>T (Jo31, rs11571302) in donors of HSTC and occurrence of aGvH disease in recipients after allogeneic hematopoietic stem cell transplantation. Altogether 136 donors of HSCT (58- related donors, 88 haploidentical unrelated donors) were genotyped for all polymorphisms using allelic discrimination methods with the TaqManÒ SNP Genotyping Assay.
In patients without aGvHD and in patients with aGvHD grade I-IV the similar distribution of alleles and genotypes for all investigated polymorphisms in donors was observed. However, we have noticed trend toward increased frequency of CT60 [G] donor allele among recipients with aGvHD I-IV (0.48 vs. 0.39, p=0.1, OR 1.49, 95% CI: 0.90–2.49) compared to recipients without aGvHD in whole group of patients. In patients transplanted from related donor also increased risk of aGvHD grade I-IV was observed for CT60 [G] donor allele (0.75 vs. 0.55, p=0.09, OR 2.11, 95%CI: 0.88–5.26). In contrary the frequencies of CT60 [G] donor allele in patients transplanted from unrelated donors are similar in recipients with and without aGvH symptoms. Haplotype estimation analysis indicated that donor haplotype CTLA-4c.49A>G[A], CTLA-4g.319C>T[C], CT60 [A], Jo31 [T] tended to be protective against aGvHD grade I-IV in whole studied group of patients (0.28 vs. 0.40, p=0.06, OR 0.60, 95% CI: 0.36–1.02) This association reach statistical significance in recipients of related transplantation (0.18 vs. 0.43, p=0.01, OR 0.29, 95% CI: 0.14–0.97)
Our study indicated that donor CT60 polymorphism might be associated with occurrence of aGvHD, especially in recipients transplanted from HLA-identical sibling donors.
Disclosures:
No relevant conflicts of interest to declare.
Early T Cell Activation Metrics Predict Graft-versus-Host Disease in a Humanized Mouse Model of Hematopoietic Stem Cell Transplantation