Faculty Bibliography

To control tuberculosis worldwide, the burden of adult pulmonary disease must be reduced. Although widely used, Mycobacterium bovis BCG vaccination given at birth does not protect against adult pulmonary disease. Therefore, postexposure vaccination of adults with mycobacterial antigens is being considered. We examined the effect of various mycobacterial antigens on mice with prior M. tuberculosis infection. Subcutaneous administration of live or heat-treated BCG with or without lipid adjuvants to infected mice induced increased antigen-specific T-cell proliferation but did not reduce the bacterial load in the lungs and caused larger lung granulomas. Similarly, additional mycobacterial antigen delivered directly to the lungs by aerosol infection with viable M. tuberculosis mixed with heat-killed Mycobacterium tuberculosis (1:1) also did not reduce the bacillary load but caused increased expression of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), which was associated with larger granulomas in the lungs. When M. tuberculosis-infected mice were treated with recombinant BCG that secreted cytokines shown to reduce disease in a preinfection vaccine model, the BCG secreting TNF-alpha, and to a lesser extent, IL-2 and gamma interferon (IFN-gamma), caused a significant increase in granuloma size in the lungs. Moreover, treatment of M. tuberculosis-infected mice with recombinant murine TNF-alpha resulted in increased inflammation in the lungs and accelerated mortality without affecting the bacillary load. Taken together, these studies suggest that administration of mycobacterial antigens to mice with prior M. tuberculosis infection leads to immune activation that may exacerbate lung pathology via TNF-alpha-induced inflammation without reducing the bacillary load

Retrorectal cyst hamartoma (RCH) is a rare benign cystic lesion located in the retrorectal space. Malignancy arising in such lesions is very uncommon. In this study, 2 cases of mucinous adenocarcinoma arising in RCH are presented. In one case, dysplastic epithelium lined the cyst wall, surrounding the area of carcinoma and suggesting a dysplasia-carcinoma progression in RCH. Adenocarcinoma and the dysplastic epithelium were strongly positive for p53 and Ki-67 and showed negative staining for p21 by immunohistochemistry. These findings are suggestive of a mutation in the p53 gene in the adenocarcinoma and in dysplastic epithelium lining the cysts, similar to the dysplasia-carcinoma sequence described for the development of colonic adenocarcinoma

Scleroderma (SSc) is a fibrosing connective tissue disease that is poorly responsive to any treatment, including immune suppression. SSc shares many characteristics with chronic graft-versus-host disease (GVHD). Because the immunomodulatory drug thalidomide has proven beneficial in chronic GVHD, we studied the immune response and clinical effects of thalidomide in SSc patients. We treated 11 SSc patients with thalidomide in an open label, dose escalating, 12 week study. Histologic comparison of skin biopsies showed changes in skin fibrosis and an increase in epidermal and dermal infiltrating CD8(+) T cells with thalidomide treatment. In thalidomide-treated SSc patients, plasma levels of IL-12 and TNF-alpha increased, while plasma IL-5 and IL-10 levels remained unchanged. These changes were associated with clinical effects, including dry skin, dermal edema, transient rashes, decreased gastroesophageal reflux symptoms, and healing of digital ulcers. When SSc PBMCs activated by anti-CD3 mAb were exposed to thalidomide, increases in both production of IL-2, IL-3, GM-CSF, and IFN-gamma and T cell expression of CD40L were observed. Thalidomide therefore appears to induce immune stimulation in SSc patients in association with clinical changes. However, it remains to be shown whether long-term enhancement of immune responses in SSc patients is clinically beneficial.

In experimental mycobacterial infection, tumor necrosis factor alpha (TNF-alpha) is required for control of bacillary growth and the protective granulomatous response, but may cause immunopathology. To directly examine the positive and detrimental effects of this cytokine, a murine model was used in which different amounts of TNF-alpha were delivered to the site of infection. Mice with a disruption in the TNF-alpha gene (TNF-KO) or wild-type mice were infected with low or high doses of recombinant Mycobacterium bovis BCG that secreted murine TNF-alpha (BCG-TNF). Infection of TNF-KO mice with BCG containing the vector (BCG-vector) at a low dose led to increased bacillary load in all organs and an extensive granulomatous response in the lungs and spleen. The mice succumbed to the infection by approximately 40 days. However, when TNF-KO mice were infected with low doses of BCG-TNF, bacillary growth was controlled, granulomas were small and well differentiated, the spleen was not enlarged, and the mice survived. Infection with high inocula of BCG-TNF resulted in bacterial clearance, but was accompanied by severe inflammation in the lungs and spleen and earlier death compared to the results from the mice infected with high inocula of BCG-vector. Wild-type mice controlled infection with either recombinant strain, but showed decreased survival following high-dose BCG-TNF infection. The effects of TNF-alpha required signaling through an intact receptor, since the differential effects were not observed when TNF-alpha receptor-deficient mice were infected. The results suggest that the relative amount of TNF-alpha at the site of infection determines whether the cytokine is protective or destructive