DataSheet_1_Immunoregulatory effects of RGMb in gut inflammation.docx

Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic cell transplantation (HCT). Current strategies to prevent GvHD with immunosuppressive drugs carry significant morbidity and may affect the graft-versus-tumor (GVT) effect. Inflammatory bowel disease (IBD) is an intestinal inflammatory condition that affects more than 2 million people in the United States. Current strategies to prevent colitis with immunosuppressive drugs carry significant morbidity. Recently, Repulsive Guidance Molecule b (RGMb) has been identified as part of a signaling hub with neogenin and BMP receptors in mice and humans. In addition, RGMb binds BMP-2/4 in mice and humans as well as PD-L2 in mice. RGMb is expressed in the gut epithelium and by antigen presenting cells, and we found significantly increased expression in mouse small intestine after total body irradiation HCT conditioning. We hypothesized that RGMb may play a role in GvHD and IBD pathogenesis by contributing to mucosal inflammation. Using major-mismatched HCT mouse models, treatment with an anti-RGMb monoclonal antibody (mAb) that blocks the interaction with BMP-2/4 and neogenin prevented GvHD and improved survival compared to isotype control (75% versus 30% survival at 60 days after transplantation). The GVT effect was retained in tumor models. Using an inflammatory bowel disease dextran sulfate sodium model, treatment with anti-RGMb blocking monoclonal antibody but not isotype control prevented colitis and improved survival compared to control (73% versus 33% at 21 days after treatment) restoring gut homeostasis. Anti-RGMb mAb (9D1) treatment decreased IFN-γ and significantly increased IL-5 and IL-10 in the gut of the treated mice compared to the isotype control treated mice.</p

Antibiotics Used Prior to Endoscopic Procedures.

<p>EGD = Esophagogastroduodenoscopy.</p

Bacterial Species that Caused Endoscopy-associated Peritonitis.

<p>EGD = Esophagogastroduodenoscopy, IUD = Intrauterine device.</p

Effect of Prophylactic Antibiotics on the Incidence of Endoscopy-associated Peritonitis in Patients Undergoing Gynecologic Procedures.

a<p>No peritonitis occurred if antibiotics were used prior to these gynecologic exams, p = 0.10.</p

Effect of Prophylactic Antibiotics on the Incidence of Endoscopy-associated Peritonitis.

<p>EGD = Esophagogastroduodenoscopy.</p>a<p>Peritonitis rate was significantly higher in the non-EGD group compared with the EGD group, p<0.05.</p>b<p>Antibiotic use prior to non-EGD procedures significantly reduced the endoscopy-associated PD peritonitis rate, p<0.05.</p

Effect of Prophylactic Antibiotics on the Incidence of Endoscopy-associated Peritonitis in Patients Undergoing Non-EGD Procedures with Invasive Therapies.

a<p>Antibiotic use prior to the non-EGD procedures with invasive therapies significantly reduced the endoscopy-associated PD peritonitis rate, p<0.05.</p

Clinical outcomes in the PD patients stratified according to HS-CRP levels.

<p>Note:</p><p>Continuous variables given as mean ± standard deviation, and categorical variables, as number (percentage).</p><p>Abbreviations: PD, peritoneal dialysis; HS-CRP, high-sensitivity C-reactive protein; HD, hemodialysis.</p

Relative risk of mortality in univariate Cox regression analysis.

<p>Note:</p><p>Abbreviations: RR, relative risk; HR, hazard ratio; CI, confidence interval; HS-CRP, high-sensitivity C-reactive protein; PD, peritoneal dialysis; AST, aspartate transaminase; ALT, alanine transaminase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; HbA1c, glycated hemoglobin; iPTH, intact parathyroid hormone; CCr, creatinine clearance.</p

Demographic and laboratory characteristics of the PD patients stratified according to serum HS-CRP levels.

<p>Note:</p><p>Continuous variables given as mean ± standard deviation, and categorical variables, as number (percentage).</p><p>Abbreviations: HS-CRP, high-sensitivity C-reactive protein; PD, peritoneal dialysis; WBC, white blood cell; AST, aspartate transaminase; ALT, alanine transaminase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; HbA1c, glycated hemoglobin; iPTH, intact parathyroid hormone.</p

Kaplan–Meier technique survival (transplantation censored) curves based on serum HS-CRP levels among PD patients in the 2-year follow-up.

<p>Kaplan–Meier technique survival (transplantation censored) curves based on serum HS-CRP levels among PD patients in the 2-year follow-up.</p