ABSTRACT
Depression is a common side-effect of interferon (IFN)-alpha treatment of hepatitis C virus (HCV) infection and melanoma. Disturbances of tryptophan (TRP) metabolism might contribute to development of IFN-alpha-associated depression due to IFN-alpha-induced activation of indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme of TRP-kynurenine (KYN) metabolism. The increased frequency of high producer (T) allele of IFN-gamma (IFNG) (+874) gene, that encodes IFNG production, in depressed patients suggested that increased IDO activity might be a risk factor for depression. The present study assessed KYN/TRP ratio (KTR) as a marker of IDO activity in American Caucasian HCV patients awaiting IFN-alpha treatment. KTR did not differ between 43 patients who did and 37 patients who did not develop depression. TRP concentrations were higher in patients who experienced depression. Odds of development of depression increased with elevation of serum TRP levels from 33% (TRP levels <12000 pmol/ml) to 68% (TRP levels > 16000 pmol/ml). Elevated serum TRP may reflect the impairment of TRP conversion into serotonin in agreement with suggested link between serotonin deficiency and depression. Up-regulation of IDO might be an additional risk factor of IFN-alpha-associated depression. Future studies shall explore the causes of elevated serum TRP in relation to IFN-alpha-associated depression.
ABSTRACT
Protozoa belonging to the genus Leishmania cause the diverse forms of human leishmaniasis, which range from self-healing cutaneous ulcers to widely disseminated or disfiguring disease. Human and murine immune responses to species causing cutaneous and visceral leishmaniasis are considerably different. In murine models of cutaneous leishmaniasis the expansion of distinct CD4(+) T-cell subsets is associated with either disease prevention (TH1) or disease exacerbation (TH2). However, studies of murine visceral leishmaniasis have not shown expansion of disease-exacerbating cells during progressive disease. The latter studies have concentrated on immune responses in splenocytes from mice infected with visceralizing Leishmania species, even though the parasites are found primarily in the livers of infected mice. The histologic response to visceralizing Leishmania sp. in the liver is one of granuloma formation, which proceeds with similar kinetics in resistant C3H and susceptible BALB/c mice. We isolated hepatic granulomas from BALB/c mice infected for 6 weeks with the visceralizing parasite L. chagasi. Study of dispersed granuloma cells by FACS and in vitro cultivation with antigen showed differences between the responses of immune cells from the spleens and liver granulomas of these infected animals. A careful dissection of immune responses in hepatic granuloma cells from susceptible or resistant mice infected with L. chagasi may lead to a better understanding of murine immune responses to these important pathogens.
ABSTRACT
Granulomas usually serve to protect the host from the spread of persistent microorganisms or other enduring injurious substances. They are complex inflammatory reactions that use many immune mechanisms to control the inciting nudis. These lesions can persist for weeks, months, or even years. Thus, understanding the mechanisms that enhance, diminish, or modulate granulomas could aid in the treatment of many diseases. Moreover, experimental animal models of granulomatous inflammation allow sophisticated investigation of some disease processes not possible using human subjects. Granulomatous inflammations are chronic, composed of activated leukocytes that are selected for deposition at the site of injury. They use various effector mechanisms, delicately balanced by many immunoregulatory circuits. Under some experimental conditions, granulomas can be isolated readily from host tissue and subjected to sophisticated immunological analysis. Therefore, it is possible to dissect the actual, local control mechanisms that govern the granulomatous response. Lesions learned studying granulomas are applicable to other types of inflammation, since granulomas use immunoregulatory networks and soluble cytokines common to many inflammatory states. Using these experimental models, it is readily apparent that studies utilizing splenocytes or peripheral blood leukocytes may not reveal the true, dominant immunoregulatory mechanisms employed at sites of active inflammation. The leukocytes of spleens and blood are a mixture of cells in various stages of activation, many of which are not destined to participate in a selective immune response. Also, granulomas are sustained inflammatory reactions permitting analysis of the unique features of chronic maintenance, as opposed to acute phase inflammation.
