Classical Hodgkin's lymphoma: molecular evidence for specific alterations in circulating T lymphocytes.

OBJECTIVE: Impairment in cell-mediated immunity has long been recognized in classical Hodgkin's lymphoma (cHL). The immunosuppressive environment at the tumor site and/or a primary T-cell defect may contribute to an ineffective immune clearance of Hodgkin/Reed-Sternberg (H/R-S) cells. Here, we analyzed whether circulating T lymphocytes of cHL patients show specific alterations in gene expression with possible impact on anti-tumor immunity. MATERIAL AND METHODS: Gene expression profiles were performed from CD3+ T cells isolated from peripheral blood samples of untreated patients with cHL versus two control groups consisting of healthy donors and patients with sarcoidosis. The regulation of gene expression was confirmed in additional patients for selected genes by real-time RT-PCR. RESULTS AND CONCLUSION: Circulating T cells of cHL show a Th1 immune response likely supporting anti-tumor immunity. However, the molecular profile reveals an association between cell cycle transition/proliferation and induction of immune regulatory genes which may limit an effective anti-tumor immune response of differentiated Th1 cells.

Identification of novel regulators in T-cell differentiation of aplastic anemia patients.

BACKGROUND: Aplastic anemia (AA) is a bone marrow failure syndrome mostly characterized by an immune-mediated destruction of marrow hematopoietic progenitor/stem cells. The resulting hypocellularity limits a detailed analysis of the cellular immune response. To overcome this technical problem we performed a microarray analysis of CD3+ T-cells derived from bone marrow aspirates and peripheral blood samples of newly diagnosed AA patients and healthy volunteers. Two AA patients were additionally analyzed after achieving a partial remission following immunosuppression. The regulation of selected candidate genes was confirmed by real-time RT-PCR. RESULTS: Among more than 22,200 transcripts, 583 genes were differentially expressed in the bone marrow of AA patients compared to healthy controls. Dysregulated genes are involved in T-cell mediated cytotoxicity, immune response of Th1 differentiated T-cells, and major regulators of immune function. In hematological remission the expression levels of several candidate genes tend to normalize, such as immune regulators and genes involved in proinflammatory immune response. CONCLUSION: Our study suggests a pivotal role of Th1/Tc1 differentiated T-cells in immune-mediated marrow destruction of AA patients. Most importantly, immune regulatory genes could be identified, which are likely involved in the recovery of hematopoiesis and may help to design new therapeutic strategies in bone marrow failure syndromes.

Intestinal immunity of Escherichia coli NISSLE 1917: a safe carrier for therapeutic molecules.

The development of novel approaches that allow accurate targeting of therapeutics to the intestinal mucosa is a major task in the research on intestinal inflammation. For the first time, a live genetically modified bacterial strain has been approved by Dutch authorities as a therapeutic agent for experimental therapy of intestinal bowel disease (IBD) in humans. Genetically modified probiotics can very well be used as carriers for localized antigen delivery into the intestine. Therapeutic safety, however, of such a carrier organism, is crucial, especially when a specific probiotic strain has to be used under diseased conditions. In this study, we tested the potential of Escherichia coli NISSLE 1917 to serve as a safe carrier for targeted delivery of recombinant proteins to the intestinal mucosa. In a well-defined and very sensitive immunological system, we demonstrate that intestinal recombinant E. coli NISSLE 1917 has no effect on migration, clonal expansion and activation status of specific CD4+ T cells, neither in healthy mice nor in animals with acute colitis. Furthermore, recombinant E. coli NISSLE 1917 has no effect on the induction or breakdown of peripheral T-cell tolerance in an autoimmune environment. The excellent colonization properties of E. coli NISSLE 1917 render this strain an ideal candidate as carrier organism for gut-focused in situ synthesis of therapeutic molecules.