Il-10 Receptor deficiency – discovery of novel mutations and rescue by allogeneic hematopoietic stem cell transplantation.

Objectives and Study: Inflammatory bowel diseases (IBD) represent a heterogeneous group of chronic disorders whose molecular etiology and curative therapy remain largely elusive. We have previously identified homozygous loss-of-function mutations in interleukin-10 receptor (IL10R) genes causing severe early-onset IBD. The frequency of IL-10R mutations in pediatric IBD is unknown. Allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to induce sustained remission in a single IL-10R-deficient patient. This study addresses the molecular heterogeneity of pediatric IBD and the use of allogeneic HSCT as a curative treatment option for this intractable condition. Methods: We analyzed a cohort of 66 patients with early-onset IBD for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL-10R-deficiency was confirmed by functional assays in patients’ peripheral-blood mononuclear cells (Western blot analysis, ELISA). Standardized allogeneic HSCT was assessed as curative therapeutic option. Results: Using a candidate sequencing approach we identified 16 patients with IL-10-/IL-10R-deficiency: three patients had biallelic mutations in IL-10, five patients had mutations in IL-10R1, and eight patients had mutations in IL-10R2. Colitis in IL-10-/IL-10R-deficient patients can be associated with extraintestinal symptoms such as folliculitis (11/16 patients) and arthritis (2/16 patients). Refractory colitis became manifest in all patients within the first 3 months of life. Allogeneic HSCT was performed in five patients and induced sustained clinical remission with a median follow-up of 1.5 years. In vitro experiments confirmed reconstitution of IL-10R-mediated signaling in all transplanted patients. Conclusion: Our findings expand the spectrum of monogenetic immune disorders and provide evidence of a curative strategy in previously uncurable intestinal hyperinflammation.