Expression of a dominant T-cell receptor can reduce toxicity and enhance tumor protection of allogeneic T-cell therapy

Due to the lack of specificity for tumor antigens, allogeneic T-cell therapy is associated with graft-versus-host disease. Enhancing the anti-tumor specificity while reducing the graft-versus-host disease risk of allogeneic T cells has remained a research focus. In this study, we demonstrate that the introduction of ‘dominant’ T-cell receptors into primary murine T cells can suppress the expression of endogenous T-cell receptors in a large proportion of the gene-modified T cells. Adoptive transfer of allogeneic T cells expressing a ‘dominant’ T-cell receptor significantly reduced the graft-versus-host toxicity in recipient mice. Using two bone marrow transplant models, enhanced anti-tumor activity was observed in the presence of reduced graft-versus-host disease. However, although transfer of T-cell receptor gene-modified allogeneic T cells resulted in the elimination of antigen-positive tumor cells and improved the survival of treated mice, it was associated with accumulation of T cells expressing endogenous T-cell receptors and the development of delayed graft-versus-host disease. The in vivo deletion of the engineered T cells, mediated by endogenous mouse mammary tumor virus MTV8 and MTV9, abolished graft-versus-host disease while retaining significant anti-tumor activity of adoptively transferred T cells. Together, this study shows that the in vitro selection of allogeneic T cells expressing high levels of a ‘dominant’ T-cell receptor can lower acute graft-versus-host disease and enhance anti-tumor activity of adoptive cell therapy, while the in vivo outgrowth of T cells expressing endogenous T-cell receptors remains a risk factor for the delayed onset of graft-versus-host disease

The pathology of bone marrow transplantation in Hong Kong Chinese

The pathological lesions found in 68 successfully engrafted patients with human leucocyte antigen-matched sibling-related bone marrow transplants werereviewed retrospectively. Twenty-six (38%) patients had acute graft-versus-host disease, which was slightly less than that reported in Caucasians. Skin was a constant site of involvement (100%), followed by the gastrointestinal tract (74%) and liver (59%). There was a 74% correlation between the clinical and histological grading of cutaneous graft-versus-host disease, while that of the gastrointestinal tract was lower at 60%. Cytomegalovirus colitis was found on histological examination of two patients clinically thought to have graft-versus-host disease. Histological evidence of infection, which included viral hepatitis (n=5), disseminated cytomegalovirus infection (n=3), disseminated aspergillosis (n=2), systemic candidiasis (n=2), Pneumocystis carinii pneumonia (n=1), and bacterial pneumonia (n=1), was present in 14 patients. In addition to graft-versus-host disease and infections, there was a case of veno-occlusive disease of the liver. Histological examination is important in distinguishing graft-versus-host disease from infection and other complications in bone marrow transplantation.published_or_final_versio

Pathogenetic role of tissue factor in graft-versus-host disease

Graft-versus-host disease (GVHD) is a serious complication after allogeneic stem cell transplantation, the mechanism of it is still not elucidated. Recent findings suggest that host endothelial cells are a target of alloreactive donor cytotoxic T lymphocytes in GVHD and tissue factor (TF) plays an important role not only in coagulation-inflammation cycle, but also in transplant immunology. We postulate TF expression in vascular endothelial cells(VEC) may play an pivotal role in the pathogenesis of GVHD. TF gene andprotein expression in target organs of GVHD in aGVHD mice was significantly elevated compared to that of controls as determined by real-time PCR and Western blotting. Allogeneic CD4^+^T cell and CD8^+^T cells enhanced TF, VCAM-1, TNF-[alpha], IFN-[gamma] and IL-6 expression in TNF-[alpha] prestimulated HUVECs compared to controls as determined by flowcytometry and real-time PCR. JNK and p38MAPK mediated allogeneic T cells-induced TF expression in HUVECs. These effects were largely prevented by monoclonal antibody against TF, SB203580 and SP600125. In concert, these data provide strong evidence that upregulated TF expression is related to tissue damage caused by GVHD, TF isthe key factor in GVHD mediated by endothelial cells and allogeneic T cells-induced TF and consecutive proinflammatory cytokines expression in VEC contribute to the pathogenesis of GVHD

Non-infectious pulmonary complications of hematopoietic stem cell transplantation

Noninfectious pulmonary complications of hematopoietic stem cell transplant are currently more prevalent than infectious complications. Unfortunately, the pathophysiology basis is not completely understood. However, there is a string association with graft-versus-host disease for many of them. Therefore, an important component of their pathophysiology is likely an allo-immune response. There is much research that needs to be conducted to improve the less than optimal outcomes for these disorders

Novel elucidation and treatment of pancreatic chronic graft-versus-host disease in mice

Chronic graft-versus-host disease (cGVHD) is a severe complication of allogeneic haematopoietic stem cell transplantation. There is a growing understanding of cGVHD, and several effective therapies for cGVHD have been reported. However, pancreatic cGVHD is a potentially untapped study field. Our thought-provoking study using a mouse model of cGVHD suggested that the pancreas could be impaired by cGVHD-induced inflammation and fibrosis and that endoplasmic reticulum (ER) stress was augmented in the pancreas affected by cGVHD. These findings urged us to treat pancreatic cGVHD through reduction of ER stress, and we used 4-phenylbutyric acid (PBA) as an ER stress reducer. A series of experiments have indicated that PBA can suppress cGVHD-elicited ER stress in the pancreas and accordingly alleviate pancreatic cGVHD. Furthermore, we focused on a correlation between epithelial to mesenchymal transition (EMT) and fibrosis in the cGVHD-affected pancreas, because EMT was conceivably implicated in various fibrosis-associated diseases. Our investigation has suggested that the expression of EMT markers was increased in the cGVHD-disordered pancreas and that it could be reduced by PBA. Taken together, we have provided a clue to elucidate the pathogenic process of pancreatic cGVHD and created a potentially effective treatment of this disease using the ER stress alleviator PBA

Biomarkers in ocular chronic graft versus host disease: tear cytokine- and chemokine-based predictive model.

Producción CientíficaPurpose: To develop a tear molecule level-based predictive model based on a panel of tear cytokines and their correlation with clinical features in ocular chronic graft versus host disease (cGVHD). Methods: Twenty-two ocular cGVHD patients and 21 healthy subjects were evaluated in a controlled environmental research laboratory (CERLab). Clinical parameters were recorded, and tears were collected. Levels of 15 molecules (epidermal growth factor [EGF], IL receptor antagonist [IL-1Ra], IL-1β, IL-2, IL-6, IL-8/CXCL8, IL-10, IL-12p70, IL-17A, interferon inducible protein [IP]-10/CXCL10, IFN-γ, VEGF, TNF-α, eotaxin 1, and regulated on activation normal T cell expressed and secreted [RANTES]) were measured by multiplex-bead assay and correlated with clinical parameters. Logistic regression was used to develop a predictive model. Leave-one-out cross-validation was applied. Classification capacity was evaluated in a cohort of individuals with dry eye (DE) of other etiologies different from GVHD. Results: Epidermal growth factor and IP-10/CXCL10 levels were significantly decreased in ocular cGVHD, positively correlating with tear production and stability and negatively correlating with symptoms, hyperemia, and vital staining. Interleukin-1Ra, IL-8/CXCL8, and IL-10 were significantly increased in ocular cGVHD, and the first two correlated positively with symptoms, hyperemia, and ocular surface integrity while negatively correlating with tear production and stability. Predictive models were generated, and the best panel was based on IL-8/CXCL8 and IP-10/CXCL10 tear levels along with age and sex, with an area under the receiving operating curve of 0.9004, sensitivity of 86.36%, and specificity of 95.24%. Conclusions: A predictive model based on tear levels of IL-8/CXCL8 and IP-10/CXCL10 resulted in optimal sensitivity and specificity. These results add further knowledge to the search for potential biomarkers in this devastating ocular inflammatory disease.Ministry of Economy and Competitiveness, Madrid, Spain, SAF-2010 15631 (AES)

Minors come of age: minor histocompatibility antigens and graft-versus-host disease

AbstractMinor histocompatibility antigens (miHA) are responsible for the occurrence of graft-versus-host disease in the setting of a major histocompatibility complex matched sibling allogeneic stem cell transplantation. These miHA are peptide fragments that are associated with major histocompatibility complex class I or class II antigens. Elegant experiments have led to the molecular characterization of these antigens. Efforts to prevent graft-versus-host disease could be targeted through this pathway by matching for these miHA or by preventing antigen recognition. Alternatively, these miHA could be exploited as targets for a more potent graft-versus-malignancy effect. This area of miHA promises to continue to be an exciting area of continued research