Chronic infections affect a third of the world’s population and can cause bone marrow suppression, a severe condition that increases mortality from infection. To uncover the basis for infection-associated bone marrow suppression, we conducted repeated infection of WT mice with Mycobacterium avium. After 4–6 months, mice became pancytopenic. Their hematopoietic stem and progenitor cells (HSPCs) were severely depleted and displayed interferon gamma (IFN-γ) signaling-dependent defects in self-renewal. There was no evidence of increased HSPC mobilization or apoptosis. However, consistent with known effects of IFN-γ, transcriptome analysis pointed toward increased myeloid differentiation of HSPCs and revealed the transcription factor Batf2 as a potential mediator of IFN-γ-induced HSPC differentiation. Gain- and loss-of-function studies uncovered a role for Batf2 in myeloid differentiation in both murine and human systems. We thus demonstrate that chronic infection can deplete HSPCs and identify BATF2 as a mediator of infection-induced HSPC terminal differentiation.
To determine whether individuals with concurrent active psychiatric disease and chronic hepatitis C virus (HCV) can be treated safely and effectively with interferon-alpha.Prospective, open label study.Tertiary referral hospital.Thirty-one consecutive patients with co-existent chronic HCV and a psychiatric illness.Interferon-alpha was administered at doses of either 5 MU three times per week for 6 months (n = 17) or 5 MU daily for 6 months (n = 14).HCV-RNA in serum was measured using reverse transcriptase polymerase chain reaction. Serum alanine aminotransferase levels were assessed and liver biopsy was performed before and after 6 months of treatment and again after 6 months of follow-up.Twenty-nine of the 31 patients completed 6 months of therapy. Two patients discontinued therapy after 2 and 3 months of treatment. Serum alanine aminotransferase levels returned to normal in 22 (71%) patients. Fifteen (48%) of the 31 patients cleared HCV-RNA from their serum. Only four patients experienced a worsening of their psychiatric illness during treatment. Interferon therapy was discontinued in two of these patients.Patients with a co-existent psychiatric illness and chronic HCV can be treated successfully with interferon-alpha with the active participation of a psychiatrist and the maintenance of psychotropic drug therapy during interferon treatment.
Summary. An open label trial of GM‐CSF plus high‐dose interferon (IFN) α 2b was performed in eight patients with chronic hepatitis B infection and 16 patients with chronic hepatitis C, who either failed to clear virus with 6 months of daily high‐dose IFN (5 MU daily) therapy ( n = 22) or were considered untreatable because of advanced disease and leukopenia ( n = 2). The dose of GM‐CSF used was 500 μg subcutaneously twice weekly. The dose of IFN used was 5 MU daily. Both agents were administered for 4 months. Five of the eight hepatitis B patients and five of the 16 hepatitis C virus patients responded to combined therapy having previously failed IFN therapy alone. The hepatitis B virus responders had low entry ALT, AST, and gamma GPT levels as compared to the non‐responders. No such differences for responders and non‐responders were seen with the hepatitis C virus patients. These data suggest that the combination of GM‐CSF and IFN may be more effective at achieving viral clearance than IFN alone.
s Submitted for the 68th Annual Scientific Meeting of the American College of Gastroenterology October 10-15, 2003, Baltimore, Maryland: CLINICAL VIGNETTES: PDF Only
