Graft versus host disease (GVHD), a severe immunogenic complication of allogeneic hematopoietic stem cell transplantation (HSCT), represents the most frequent cause of transplant-related mortality (TRM). Despite a huge progress in HSCT techniques and posttransplant care, GVHD remains a significant obstacle in successful HSCT outcome. This review presents a complex summary of GVHD pathogenesis with focus on references considering basic biological processes such as DNA damage response and cellular senescence.

SUMMARYLeflunomide has been identified as an immunoregulatory and anti-inflammatory compound. Allergic disease is characterized by elevated serum IgE levels, production of allergen-specific IgE and the release of inflammatory mediators from mast cells and granulocytes. Here we demonstrate, using an in vivo murine model, the ability of leflunomide to down-regulate levels of total and allergen-specific serum IgE production. Mice receiving leflunomide (45 mg/kg) orally at the time of primary immunization with ovalbumin adsorbed to aluminium hydroxide adjuvant, showed a reduction in total serum IgE levels of 95%, 41% and 32% following primary, secondary and tertiary immunizations, respectively (P < 0·05). When leflunomide was administered both at the time of primary and subsequent immunizations, reductions in total and specific serum IgE levels of > 80% and > 38%, respectively, were observed (P < 0·05). Administration of leflunomide to mice which had already developed an IgE response resulted in reductions in total and specific serum IgE levels of > 80% and > 45%, respectively (P < 0·05). Following leflunomide treatment, animals failed to develop immediate cutaneous hypersensitivity responses when challenged intradermally with allergen. Down-regulation of immunoglobulin production was not restricted to IgE, since levels of allergen-specific IgG1 and IgG2a in serum were also reduced. The finding of significant reductions in total and allergen-specific IgM suggests that the mechanism of action does not involve selective inhibition of immunoglobulin class switching. A loss in production of the T helper cell-derived B cell differentiation factor IL-5 may account for the reduction in immunoglobulin levels. In adoptive transfer experiments leflunomide did not induce tolerance in allergen-reactive Th2 populations, contrary to animal disease models of transplantation and autoimmunity, where leflunomide was shown to induce tolerance in the effector T cell population.

Polymorphisms of genes involved in innate and adaptive immunity have become an object of major interest in regard to hematopoietic stem cell transplantation (HSCT) complications. Regimen-related gastrointestinal toxicity (RR-GIT) is the dominant complication during the pre-engraftment period and has been linked to increased risk of graft-versus-host disease (GVHD) development. According to our hypothesis, functional variants of genes participating in DNA damage response (DDR) may have an impact on the extent of tissue damage caused by the conditioning regimen. In our single-center study, we analyzed 62 patients who underwent HSCT from HLA-identical donors after reduced conditioning. The patients were genotyped for 5 single nucleotide polymorphisms (SNPs, rs4585 T/G, rs189037 A/G, rs227092 T/G, rs228590 C/T, and rs664677 T/C) of the ATM gene-the essential member of the DDR pathways, using allele-specific matrix-assisted laser desorption/ionization, time-of-flight (MALDI-TOF) mass spectrometry assay. Because of almost absolute linkage disequilibrium observed among all 5 SNPs, association of 2 major ATM haplotypes (ATM1/ATM2) with RR-GIT and acute GVHD (aGVHD) was analyzed. Importantly, the univariate and multivariate analysis showed that patients homozygous for ATM2 haplotype (rs4585*T, rs189037*A, rs227092*T, rs228590*C, and rs664677*T) are more likely to suffer from high-grade RR-GIT than ATM1 homozygous patients. The association with aGVHD was not significant. To our knowledge, this is the first report showing the ATM gene variability in relation to RR-GIT in the allogeneic HSCT setting.

Background. Acute promyelocytic leukaemia (APL) is a subtype of acute myeloid leukaemia with high curability rates. However, it is often accompanied by severe coagulopathy and bleeding risk and thus represents a potentially fatal haematological emergency requiring immediate treatment. Spontaneous splenic rupture is a rare event in all haematological malignancies. Only two clinical cases have been described so far in a setting of APL. Case report. We report a patient with APL without preceding splenomegaly who underwent urgent splenectomy for spontaneously occurring splenic rupture during induction chemotherapy. After surgery the patient completed induction chemotherapy and achieved complete remission. Conclusion. This is the second case of spontaneous splenic rupture without preceding splenomegaly in a patient with APL during induction chemotherapy described so far. Our case demonstrates that emergent splenectomy can be lifesaving even in the unfavourable condition of patient with severe immune deficiency.

Presented are results of allogeneic hematopoietic stem cell transplantations (HSCTs) in 13 patients with high-risk acute lymphoblastic leukemia (ALL) in the first complete remission after a reduced intensity conditioning combining fludarabine (150 mg/m2) and melphalan (140 mg/m2) with thymoglobulin (4.5 mg/kg). The immunosuppressive effect of T-cell depletion reducing the risk of graft-versus-host disease (GVHD) and non-relapse mortality was compensated by early initiation of reduction and withdrawal of prophylactic immunosuppression aimed at maintaining effective immunological antileukemic control. The median post-transplant follow-up was 23 (range, 10-65) months. Stable engraftment of donor's hematopoiesis was achieved in all patients. Acute GVHD was observed in two cases (15.4%); the chronic form was not noted. Two patients (15.4%) relapsed with ALL at 3 and 16 months after transplantation. During the above post-transplant follow-up, all 13 recipients were alive, with a probability of 2-year disease-free survival of 76.9% (95% CI 51-100%). Although the results were obtained with a small pilot study group it may be assumed that, given the prognostic risk of most patients and the nearly 2-year median post-transplant follow-up, the approach may be considered as an alternative to HSCTs after traditional myeloablative or reduced conditioning regimens with standard GVHD prophylaxis.