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Objectives: The oral cavity commonly displays mucosal lichenoid lesions and salivary gland dysfunction, which are considered different chronic Graft-versus-Host Disease (cGVHD) patho-physiology's. However, diagnostics of salivary gland (sg-)cGVHD are limited. The objectives of the current study are to evaluate the minor salivary gland (MSG) histo-immunopathological profiles post allogenic hematopoietic cell transplantation based on sg-cGVHD criteria. Design: Histopathology was characterized according to two published grading strategies. Firstly, the National Institute of Health (NIH) assessed peri-ductal/acinar infiltration, exocytosis, damage, and fibrosis, and a points-based grading scheme was established (0-16 points, Grade (G) 0 to IV). Second, a modified Sjo center dot gren's Syndrome focus-score with parenchymal damage was also adapted, (0-10 points, Score 0 to 2). 146 MSG biopsies from 79 patients were compared, using the his-topathological specific criteria for sg-cGVHD pathology. Quantitative immunohistochemistry for T-cells (CD4, CD8), B-cells (CD19, CD20), monocytic cells (CD68) and dendritic cells (CD1a) were also assessed. Results: The large-scale cohort validated the use of both grading schemes. GIII-GIV and score 2 signified a histopathological diagnosis of "likely" sg-cGVHD. Immunopathological severity was associated with increased T-cells (CD4 and CD8) and monocytic (CD68) infiltrate, with minimal involvement of B-cells (CD19 and CD20), and Langerhans cells (CD1a). Conclu-sions: Both schemes were verified as being suitable for histological grading to improve assess-ment and diagnosis of sg-cGVHD. The NIH cGVHD grading appears to be more beneficial for research purposes, including final diagnostics of "no/inactive", "possible" or "likely" cGVHD. The study highlights the intricacies of sg-cGVHD pathology; and the need for standardized assessment to improve patient management associated to sg-cGVHD.

Objectives: The oral cavity commonly displays mucosal lichenoid lesions and salivary gland dysfunction, which are considered different chronic Graft-versus-Host Disease (cGVHD) patho-physiology's. However, diagnostics of salivary gland (sg-)cGVHD are limited. The objectives of the current study are to evaluate the minor salivary gland (MSG) histo-immunopathological profiles post allogenic hematopoietic cell transplantation based on sg-cGVHD criteria. Design: Histopathology was characterized according to two published grading strategies. Firstly, the National Institute of Health (NIH) assessed peri-ductal/acinar infiltration, exocytosis, damage, and fibrosis, and a points-based grading scheme was established (0-16 points, Grade (G) 0 to IV). Second, a modified Sjo center dot gren's Syndrome focus-score with parenchymal damage was also adapted, (0-10 points, Score 0 to 2). 146 MSG biopsies from 79 patients were compared, using the his-topathological specific criteria for sg-cGVHD pathology. Quantitative immunohistochemistry for T-cells (CD4, CD8), B-cells (CD19, CD20), monocytic cells (CD68) and dendritic cells (CD1a) were also assessed. Results: The large-scale cohort validated the use of both grading schemes. GIII-GIV and score 2 signified a histopathological diagnosis of "likely" sg-cGVHD. Immunopathological severity was associated with increased T-cells (CD4 and CD8) and monocytic (CD68) infiltrate, with minimal involvement of B-cells (CD19 and CD20), and Langerhans cells (CD1a). Conclu-sions: Both schemes were verified as being suitable for histological grading to improve assess-ment and diagnosis of sg-cGVHD. The NIH cGVHD grading appears to be more beneficial for research purposes, including final diagnostics of "no/inactive", "possible" or "likely" cGVHD. The study highlights the intricacies of sg-cGVHD pathology; and the need for standardized assessment to improve patient management associated to sg-cGVHD.

__Objective:__ No standard second‐line treatment exists for acute graft‐versus‐host disease steroid‐refractory (SR‐aGvHD), and long‐term outcomes remain poor. Mesenchymal stromal cells (MSCs) have been evaluated as treatment, but no disease model (DM) exists that integrates and extrapolates currently available evidence. The aim of this study was to develop such a DM to describe the natural history of SR‐aGvHD and to predict long‐term outcomes. __Method:__ The DM was developed in collaboration with experts in haematology‐oncology. Subsequently, a model simulation was run. Input parameters for transition and survival estimates were informed by published data of clinical trials on MSC treatment for SR‐aGvHD. Parametric distributions were used to estimate long‐term survival rates after MSCs. __Results:__ The newly developed DM is a cohort model that consists of eight health states. For the model simulation, we obtained data on 327 patients from 14 published phase II trials. Due to limited evidence, DM structure was simplified and several assumptions had to be made. Median overall survival was 3.2 years for complete response and 0.5 years for no complete response. __Conclusion:__ The DM provides a comprehensive overview on the second‐line treatment pathway for aGvHD and enables long‐term predictions that can be used to perform a cost‐effectiveness analysis comparing any treatment for SR‐aGvHD.

Objective: No standard second-line treatment exists for acute graft-versus-host disease steroid-refractory (SR-aGvHD), and long-term outcomes remain poor. Mesenchymal stromal cells (MSCs) have been evaluated as treatment, but no disease model (DM) exists that integrates and extrapolates currently available evidence. The aim of this study was to develop such a DM to describe the natural history of SR-aGvHD and to predict long-term outcomes. Method: The DM was developed in collaboration with experts in haematology-oncology. Subsequently, a model simulation was run. Input parameters for transition and survival estimates were informed by published data of clinical trials on MSC treatment for SR-aGvHD. Parametric distributions were used to estimate long-term survival rates after MSCs. Results: The newly developed DM is a cohort model that consists of eight health states. For the model simulation, we obtained data on 327 patients from 14 published phase II trials. Due to limited evidence, DM structure was simplified and several assumptions had to be made. Median overall survival was 3.2 years for complete response and 0.5 years for no complete response. Conclusion: The DM provides a comprehensive overview on the second-line treatment pathway for aGvHD and enables long-term predictions that can be used to perform a cost-effectiveness analysis comparing any treatment for SR-aGvHD.

Objective No standard second?line treatment exists for acute graft?versus?host disease steroid?refractory (SR?aGvHD), and long?term outcomes remain poor. Mesenchymal stromal cells (MSCs) have been evaluated as treatment, but no disease model (DM) exists that integrates and extrapolates currently available evidence. The aim of this study was to develop such a DM to describe the natural history of SR?aGvHD and to predict long?term outcomes. Method The DM was developed in collaboration with experts in haematology?oncology. Subsequently, a model simulation was run. Input parameters for transition and survival estimates were informed by published data of clinical trials on MSC treatment for SR?aGvHD. Parametric distributions were used to estimate long?term survival rates after MSCs. Results The newly developed DM is a cohort model that consists of eight health states. For the model simulation, we obtained data on 327 patients from 14 published phase II trials. Due to limited evidence, DM structure was simplified and several assumptions had to be made. Median overall survival was 3.2 years for complete response and 0.5 years for no complete response. Conclusion The DM provides a comprehensive overview on the second?line treatment pathway for aGvHD and enables long?term predictions that can be used to perform a cost?effectiveness analysis comparing any treatment for SR?aGvHD.

When compared with BMT, umbilical cord blood transplantation (UCBT) is associated with a lower rate of engraftment and delayed hematological/immunological recovery. This leads to increased risk of TRM in the early post transplantation period due to infection. Acute GVHD, although occurring less frequently in UCBT compared with BMT, is also significantly associated with increased rate of early TRM. BM MSCs are known to support normal in vivo hematopoiesis, and co-transplantation of MSCs has been shown to enhance engraftment of human cord blood hematopoietic cells in nonobese diabetic/SCID mice. In 13 children with hematological disorders (median age 2 years) undergoing UCBT, we co-transplanted paternal, HLA-disparate MSCs with the aim of improving hematological recovery and reducing rejection. We observed no differences in hematological recovery or rejection rates compared with 39 matched historical controls, most of whom received G-CSF after UCBT. However, the rate of grade III and IV acute GVHD was significantly decreased in the study cohort when compared with controls (P = 0.05), thus resulting in reduced early TRM. Although these data do not support the use of MSCs in UCBT to support hematopoietic engraftment, they suggest that MSCs, possibly because of their immunosuppressive effect, may abrogate life-threatening acute GVHD and reduce early TRM. Bone Marrow Transplantation (2011) 46, 200-207; doi: 10.1038/bmt.2010.87; published online 19 April 2010

Besides the immune regulatory role of mesenchymal stem cells, in models of experimental injury, intravenous administration of these cells improves organ healing, mainly through paracrine effects and a shift from the production of proinflammatory to anti-inflammatory cytokines at the site of injury.2,3 Furthermore, we have previously shown that immune reconstitution improves after mesenchymal stem-cell infusion, with resolution of graft-versus-host disease and subsequent tapering of immunosuppressive drugs.4 However, we acknowledge that the present study is insufficiently powered to exclude an effect of mesenchymal stem cells on the rate of infections.

Seven patients underwent treatment with mesenchymal stem cells (MSCs), together with allogeneic hematopoietic stem cell transplantation (HSCT). MSCs were given to three patients for graft failure and four patients were included in a pilot study. HSCT donors were three human leukocyte antigen (HLA)-identical siblings, three unrelated donors and one cord blood unit. The conditioning was myeloablative in four patients and reduced in three patients. MSC donors were HLA-identical siblings in three cases and haploidentical in four cases. Neutrophil counts >0.5 ×109/l was reached at a median of 12 (range 10-28) days. Platelet counts >30 x 109/l was achieved at a median of 12 (8-36) days. Acute graft-versus-host disease (GVHD) grade 0-l was seen in five patients. Two patients developed grade II, which in one patient evolved into chronic GVHD. One severe combined immunodeficiency (SCID) patient died of aspergillosis, the others are alive and well. One patient, diagnosed with aplastic anemia had graft failure after her first transplantation and severe Henoch-Schönlein Purpura (HSP). After retransplantation of MSCs and HSCs, she recovered from both the HSP and aplasia. Thus, co-transplantation of MSC resulted in fast engraftment of absolute neutrophil count (ANC) and platelets and 100% donor chimerism, even in three patients regrafted for graft failure/rejection.

Mesenchymal stem cells (MSC) have immunomodulatory effects and inhibit T-cell responses to alloantigens and mitogens in vitro and in vivo. We wanted to examine the effect of MSC on human B cells. MSC stimulated IgG production, measured in an enzyme-linked immunospot (ELIspot) assay in blood and spleen lymphocytes. MSC only induced a low proliferation. When a semipermeable membrane separated MSC and mononuclear cells, the IgG production was stimulated in unfractionated lymphocytes. In contrast, enriched B cells required cell contact with MSC to produce IgG. Co-cultures of MSC and lymphocytes increased IFN-γ production. MSC produce IL-6, and addition of MSC to spleen cells dramatically increased IL-6 levels. After lymphocyte stimulation with lipopolysaccharide (LPS), cytomegalovirus or varicella zoster virus, MSC either stimulated or inhibited IgG response, depending on the level of stimulation by LPS or the viral antigens. Similar results were obtained for enriched B cells. To conclude, MSC stimulate B-cell antibody secretion. The IgG secretion by activated B cells may be stimulated or inhibited by the addition of MSC, depending on the level of stimulation.

OBJECTIVE/HYPOTHESIS: The aim of this study was to analyze the short-term viscoelastic and histologic properties of scarred rabbit vocal folds after injection of human mesenchymal stem cells (MSC) as well as the degree of MSC survival. Because MSCs are antiinflammatory and regenerate mesenchymal tissues, can MSC injection reduce vocal fold scarring after injury? STUDY DESIGN: Twelve vocal folds from 10 New Zealand rabbits were scarred by a localized resection and injected with human MSC or saline. Eight vocal folds were left as controls. MATERIAL AND METHODS: After 4 weeks, 10 larynges were stained for histology and evaluation of the lamina propria thickness. Collagen type I content was analyzed from six rabbits. MSC survival was analyzed by fluorescent in situ hybridization staining from three rabbits. Viscoelasticity for 10 vocal folds was analyzed in a parallel-plate rheometer. RESULTS: The rheometry on fresh-frozen samples showed decreased dynamic viscosity and lower elastic modulus (P<.01) in the scarred samples injected with MSC as compared with the untreated scarred group. Normal controls had lower dynamic viscosity and elastic modulus as compared with the scarred untreated and treated vocal folds (P<.01). Histologic analysis showed a higher content of collagen type 1 in the scarred samples as compared with the normal vocal folds and with the scarred folds treated with MSC. MSCs remained in all samples analyzed. CONCLUSIONS: The treated scarred vocal folds showed persistent MSC. Injection of scarred rabbit vocal folds with MSC rendered improved viscoelastic parameters and less signs of scarring expressed as collagen content in comparison to the untreated scarred vocal folds.