Exploratory Study of Predicted Indirectly ReCognizable HLA Epitopes in Mismatched Hematopoietic Cell Transplantations

HLA-mismatches in hematopoietic stem-cell transplantation are associated with an impaired overall survival (OS). The aim of this study is to explore whether the Predicted Indirectly ReCognizable HLA-Epitopes (PIRCHE) algorithm can be used to identify HLA-mismatches that are related to an impaired transplant outcome. PIRCHE are computationally predicted peptides derived from the patient’s mismatched-HLA molecules that can be presented by donor-patient shared HLA. We retrospectively scored PIRCHE numbers either presented on HLA class-I (PIRCHE-I) or class-II (PIRCHE-II) for a Dutch multicenter cohort of 103 patients who received a single HLA-mismatched (9/10) unrelated donor transplant in an early phase of their disease. These patients were divided into low and high PIRCHE-I and PIRCHE-II groups, based on their PIRCHE scores, and compared using multivariate statistical analysis methods. The high PIRCHE-II group had a significantly impaired OS compared to the low PIRCHE-II group and the 10/10 reference group (HR: 1.86, 95%-CI: 1.02–3.40; and HR: 2.65, 95%-CI: 1.53–4.60, respectively). Overall, PIRCHE-II seem to have a more prominent effect on OS than PIRCHE-I. This impaired OS is probably due to an increased risk for severe acute graft-vs.-host disease. These data suggest that high PIRCHE-II scores may be used to identify non-permissible HLA mismatches within single HLA-mismatched hematopoietic stem-cell transplantations

The number of T cell allo-epitopes associates with CD4+and CD8+T-cell infiltration in pediatric cutaneous GVHD

Transplantation and immunomodulatio

The number of T cell allo-epitopes associates with CD4+ and CD8+ T-cell infiltration in pediatric cutaneous GVHD

Risk factors for graft-versus-host disease (GVHD) following allogeneic hematopoietic stem-cell transplantation (HCST) include: HLA mismatches, sex-mismatch, and stem-cell source. We retrospectively analyzed if HLA- and sex-mismatching quantitatively affects the composition of GVHD-induced T-cell infiltrates. We quantified absolute numbers of CD4+ and CD8+ T cells present in tissue sections from skin biopsies of 23 pediatric HSCT-recipients with GVHD. HSCT with a sex-mismatched unrelated donor was associated with an increased number of CD4+ T cells when compared to a sex-matched unrelated donor (p=0.01). The absolute numbers of skin-infiltrating T cells were increased in patients expressing T-cell epitopes derived from the recipient's mismatched HLA, so called predicted indirectly recognizable HLA epitopes (PIRCHE). The combined expression of PIRCHE with a sex-mismatch resulted in the highest number of skin-infiltrating T cells. Our results indicate that an increased number of recipient-specific T-cell epitopes is associated with accumulation of CD4+ and CD8+ T cells in the skin

Ergometric endurance capacity of patients with chronic low back pain in a multimodal treatment program

We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.Leukemia advance online publication, 8 May 2015; doi:10.1038/leu.2015.89