Pathogenesis Of aGVHD Research Articles

Effect of IL-18 and sIL2R on aGVHD occurrence after hematopoietic stem cell transplantation in some Iranian patients

Background Graft-versus-host disease is one of the major complications after allogeneic bone marrow transplantation, but it is not easy to anticipate the onset. Cytokines released by type 1 T helper cells are thought to play a pivotal role in acute graft-versus-host disease aGVHD. The ability to predict the likely occurrence of graft-versus-host-disease (GVHD) after Hematopoietic Stem cell Transplantation (HSCT) would be extremely valuable. By serially measuring serum levels of soluble IL-2 receptor (sIL-2R), IL-18 and following allogeneic HSCT we tried to define their effect on aGVHD as a complication of transplantation and determine useful markers for aGVHD predictors. Samples and methods Serum sIL-2R, IL-18, levels were measured by sandwich ELISA in 219 sera samples from 39 patients (with hematological disorders before and after allogeneic HSCT) and 28 controls. All patients received transplants from HLA-identical siblings. Results 23 (58.9%) patients developed aGVHD (I–IV) and serum levels of sIL-2R and IL-18, in sera drawn before transplantation, in patients with acute graft-versus-host disease (aGVHD +), were increased in comparison to patients without acute graft-versus-host disease (aGVHD −) and to a control group and there were no significant differences in serum levels of sIL-2R and IL-18 in aGVHD − patients and controls. Serum level of IL-18, in aGVHD + patients, was increased during days 3–24 after HSCT, and there was a significant difference according to GVHD severity. In majority of patients with acute GVHD (60%), the peak levels of IL-18 and sIL-2R were achieved on day 10 after HSCT and the rise in sIL-2R and IL-18 preceded the clinical signs of GVHD (mean day 15 after BMT). The level of IL-18 in patients with aGVHD strongly correlated with the severity of aGVHD on Day 10 after HSCT. IL-18 level (before HSCT), in patients who received Busulfan and Fludarabin which were used to treat aGVHD, was lower than in patients who received Busulfan and Cyclophosphamide. Conclusion Our data concluded that IL-18 plays an important role in the development of aGVHD and the IL-18 level might be an indicator of aGVHD, reflecting the severity of the disease. These findings suggest that IL-18 may play an important role in the pathogenesis of aGVHD and that measurement of serum IL-18 levels can be a useful indicator of aGVHD.

Cytokine expression during acute graft-versus-host disease after allogeneic peripheral stem cell transplantation

Acute graft-versus-host disease (aGVHD) is one of the major problems following allogeneic peripheral blood stem cell transplantation (allo-PBSCT). In order to investigate the pathogenesis of human aGVHD, we analyzed cytokine gene expression and cytokine secretion by peripheral blood mononuclear cells (PBMC) in 30 patients who underwent allo-PBSCT. In this study, reverse transcription-polymerase chain reaction (RT-PCR) was used to explore the mRNA expression of interleukin (IL)-2, interferon (IFN)-gamma, IL-4, IL-10 and IL-12 in the PBMC of allo-PBSCT patients with aGVHD and in controls. The concentrations of these cytokines and of IL-18 were also measured by means of ELISA in medium obtained from cultured leukocytes after stimulation with PHA or LPS. Compared with the normal allo-PBSCT group (n=14), IL-2 and IFN-gamma were detected more frequently in aGVHD group (n=16). IL-12 and IL-18 were elevated, while IL-10 level decreased in the same group. There is no difference in IL-4 gene expression between patients with or without aGVHD, but the concentration of IL-4 for patients with grade II-IV aGVHD decreased. These data suggest that IL-2, IFN-gamma, IL-12 and IL-18 play important roles in the development of aGVHD in humans.

Patient interleukin-18 GCG haplotype associates with improved survival and decreased transplant-related mortality after unrelated-donor bone marrow transplantation.

Interleukin-18 (IL-18), a proinflammatory cytokine, is elevated in patients with acute graft-versus-host disease (aGVHD). IL-18 induces Th1 differentiation and cytotoxic T-lymphocyte function, both of which have been implicated in the pathogenesis of aGVHD. However, recent studies have shown that neutralization of IL-18 by antibodies leads to an increased risk of aGVHD-related mortality while administration of IL-18 significantly improved survival. We have genotyped a cohort of 157 patient/donor pairs undergoing unrelated donor bone marrow transplantation (BMT) for three polymorphisms recently identified in the promoter of the IL-18 gene: G-137C, C-607A and G-656T. Using phase software, three main haplotypes were reconstructed: GCG, CAT and GAT. We found no association between the occurrence of aGVHD and patient/donor haplotypes. The presence of the GCG haplotype in patients was associated with significantly decreased risk of transplant-related mortality at 100 d (23% in patients with GCG vs. 48% in patients without GCG, P < 0.01) and at 1 year (36% vs. 65%, P < 0.01). The presence of the GCG haplotype in patients was also associated with improved survival (57% vs. 32%, P < 0.01). Cox regression analysis showed that the presence of the GCG haplotype was associated with a twofold increased probability of survival. These data suggest that the IL-18 promoter GCG haplotype may influence survival after unrelated donor BMT without altering the risk of aGVHD.

Elevated interleukin (IL)-18 levels during acute graft-versus-host disease after allogeneic bone marrow transplantation.

Acute graft-versus-host disease (aGVHD) after allogeneic bone marrow transplantation (BMT) is mediated by grafted T lymphocytes after their polarization into type 1 T cells. Interleukin (IL)-18, a novel immunoregulatory cytokine, strongly stimulates type 1 T cells, therefore we postulated that IL-18 may be involved in the pathogenesis of aGVHD. Using an enzyme-linked immunosorbent assay (ELISA), we serially measured serum levels of IL-18 in 37 patients with haematological malignancy before and after allogeneic BMT. Patients with aGVHD had high levels of IL-18 that strongly correlated with the severity of aGVHD. We also found that they showed reduced serum levels of IL-18 after appropriate treatment or at a state of resolution. IL-18 levels were not affected by the pretransplant regimen, engraftment or bacterial infection. Compared with circulating interferon (IFN)-gamma or IL-12 levels, serum levels of IL-18 showed a more sensitive and specific correlation with the disease status of aGVHD. These findings suggest that IL-18 may play important roles in the pathogenesis of aGVHD and that measurement of serum IL-18 levels can be useful indicator of aGVHD.

Increased soluble Fas-ligand in sera of bone marrow transplant recipients with acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is a major complication following allogeneic bone marrow transplantation (BMT). Recently, accumulating evidence indicates that the Fas/Fas ligand (FasL) system is implicated in the pathogenesis of aGVHD in murine models. We determined the serum levels of soluble FasL (sFasL) in BMT recipients using an enzyme-linked immunosorbent assay. The serum sFasL was suppressed during the period of myelosuppression following the preparative regimen and subsequently increased with hematopoietic reconstitution after BMT. In patients with aGVHD, the serum sFasL level was significantly higher than in those without aGVHD. In the mixed lymphocyte reaction assay, sFasL in the supernatants was increased with a significant correlation to the level of 3H-thymidine uptake. Our findings suggest that the Fas/FasL system is activated by allogeneic stimulation and may have close correlation to the development of aGVHD in human BMT.

ROLE OF NATURAL KILLER CELLS IN THE PATHOGENESIS OF HUMAN ACUTE GRAFT-VERSUS-HOST DISEASE

Clinical acute graft-versus-host disease (aGVHD) was correlated with alterations in PBL phenotype and skin immunohistology in 52 patients transplanted with HLA-identical bone marrow. Concurrent with the emergence of aGVHD, there was a profound decrease in absolute number of CD3- T cells and an increase in CD3-CD16+, CD56+ (a subset of which coexpress CD8+ "dim") NK cells in the PBL. CD4+ T and CD20+ B lymphocytes failed to recover within 90 days in the patients with grades II-IV aGVHD. Ex vivo partial T cell depletion, in itself, did not significantly impair T cell recovery as compared to that in non-T-depleted recipients unless aGVHD occurred. Although leukocytic cellular infiltration in the skin was generally sparse, CD16+ NK lymphocytes were significantly increased in grades II-IV aGVHD. By contrast, there was no significant increase in CD3+, CD4+, or CD8+ lymphocytes in these lesions as compared to skin biopsies obtained from BMT patients without aGVHD or from normal skin. Taken together, these findings suggest that NK cells may be important in the pathogenesis of human aGVHD.