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Acute graft-versus-host disease (GVHD) targets the crypts in the gastrointestinal (GI) tract that are responsible for the self-renewal of the intestinal mucosa. Recent advances in the identification and culture of intestinal stem cells have improved our understanding of the interactions between the microbiome and the immune system (both innate and adaptive) that are key to the pathophysiology of GVHD. The identification of serum biomarkers that best predict long-term GVHD outcomes derive from the GI tract and have focused attention on cellular elements that act as shields against GVHD as well as its targets. These biomarkers have illuminated new mechanisms of crypt biology and provided insights that should prove useful both in the design of clinical trials and as guides to GVHD prevention and treatment.

Acute graft-versus-host disease (GVHD) targets the crypts in the gastrointestinal (GI) tract that are responsible for the self-renewal of the intestinal mucosa. Recent advances in the identification and culture of intestinal stem cells have improved our understanding of the interactions between the microbiome and the immune system (both innate and adaptive) that are key to the pathophysiology of GVHD. The identification of serum biomarkers that best predict long-term GVHD outcomes derive from the GI tract and have focused attention on cellular elements that act as shields against GVHD as well as its targets. These biomarkers have illuminated new mechanisms of crypt biology and provided insights that should prove useful both in the design of clinical trials and as guides to GVHD prevention and treatment.

Acute graft-versus-host disease (GVHD) targets the crypts in the gastrointestinal (GI) tract that are responsible for the self-renewal of the intestinal mucosa. Recent advances in the identification and culture of intestinal stem cells have improved our understanding of the interactions between the microbiome and the immune system (both innate and adaptive) that are key to the pathophysiology of GVHD. The identification of serum biomarkers that best predict long-term GVHD outcomes derive from the GI tract and have focused attention on cellular elements that act as shields against GVHD as well as its targets. These biomarkers have illuminated new mechanisms of crypt biology and provided insights that should prove useful both in the design of clinical trials and as guides to GVHD prevention and treatment.

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P< .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P= .004) and for Minnesota risk (0.72, P= .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.

ABSTRACTPerforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with a fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), in infants. More recently, it has also been recognized that partial loss of perforin function can cause disease in later life, including delayed onset FHL2 and haematological malignancies. Herein, we report a family in which a wide range of systemic inflammatory and neoplastic manifestations have occurred across three generations. We found that disease was linked to two missense perforin gene mutations (encoding A91V, R410W) that cause protein misfolding and partial loss of activity. These cases link the partial loss of perforin function with some solid tumors that are known to be controlled by the immune system, as well as haematological cancers. Our findings also demonstrate that perforin gene mutations can contribute to hereditary cancer predisposition.