Faculty Bibliography

Activated T cells may express FOXP3. It is thought that FOXP3 is not a specific marker to determine regulatory T cells (Treg) in humans. Here, we examined the functional phenotype and cytokine profile of the in vitro induced FOXP3(+) T cells, primary FOXP3(+) and FOXP3(-) T cells in patients with ulcerative colitis and tumors including colon carcinoma, melanoma, hepatic carcinoma, ovarian carcinoma, pancreatic cancer, and renal cell carcinoma. We observed similar levels of suppressive capacity of primary FOXP3(+) T cells in blood, tumors, and colitic tissues. Compared with primary FOXP3(-) T cells in the same microenvironment, these primary FOXP3(+) T cells expressed minimal levels of effector cytokines, negligible amount of cytotoxic molecule granzyme B, and levels of suppressive molecules interleukin-10 and PD-1. Although the in vitro activated T cells expressed FOXP3, these induced FOXP3(+) T cells expressed high levels of multiple effector cytokines and were not functionally suppressive. The data reinforce the fact that FOXP3 remains an accurate marker to define primary Tregs in patients with cancer and autoimmune disease. We suggest that the combination of FOXP3 and cytokine profile is useful for further functionally distinguishing primary Tregs from activated conventional T cells.

The incidence of hepatocellular carcinoma (HCC) is rising, and the number of patients with HCC is expected to more than double over the next 1 to 2 decades. HCC meets the criteria for establishment of a surveillance program. Patients with cirrhosis, regardless of the cause, are at the highest risk for developing HCC and this is the population in which surveillance should be performed. (Alpha-fetoprotein and hepatic ultrasonography are the currently recommended surveillance tests. If a surveillance test is abnormal, there is a need for a recall test for diagnostic evaluation of HCC. Triple-phase imaging is recommended for evaluation at recall, with MRI being more sensitive and specific. Novel genetic markers can improve the histologic diagnosis of early HCC. The Barcelona staging classification is the best system for determining the prognosis of patients and it is linked to an evidence-based treatment algorithm. Resection, transplantation, and percutaneous ablation are considered curative interventions and are currently applied to about 30% of all patients with HCC.

Cholangiocarcinoma is a rare malignancy arising from the bile duct epithelium with a grim prognosis. Although complete resection may be curative, it is feasible only in a minority of cases owing to local extension of the tumor. Early experiences with liver transplantation were discouraging, given the high rates of tumor recurrence and poor patient survival. Trials with aggressive transplantation methods and adjuvant chemotherapy did not yield significantly better outcomes. Recently, stringent patient selection and neoadjuvant chemoradiation have yielded promising results with 5-year survival rates as high as 76%. Factors associated with recurrence after transplantation include advanced age, history of cholecystectomy, elevated serum glycoprotein cancer antigen 19-9 level, a discreet mass on imaging and an interval from enrollment to transplant greater than 100 days.

Th1 and Th17 T cells are often colocalized in pathological environments, yet Th1-derived IFN-gamma inhibits Th17 cell development in vitro. We explored the physiologic basis of this paradox in humans. In this study, we demonstrate increased the number of CD4(+) and CD8(+) IL-17(+) T cells in skin lesions of psoriasis. Furthermore, we show that myeloid APCs potently support induction of IL-17(+) T cells, and that this activity is greatly increased in psoriasis. We tested stimuli that might account for this activity. Th1 cells and IFN-gamma are increased in psoriatic blood and lesional skin. We show that IFN-gamma programs myeloid APCs to induce human IL-17(+) T cells via IL-1 and IL-23. IFN-gamma also stimulates APC production of CCL20, supporting migration of IL-17(+) T cells, and synergizes with IL-17 in the production of human beta-defensin 2, an antimicrobial and chemotactic protein highly overexpressed by psoriatic keratinocytes. This study reveals a novel mechanistic interaction between Th1 and IL-17(+) T cells, challenges the view that Th1 cells suppress Th17 development through IFN-gamma, and suggests that Th1 and IL-17(+) T cells may collaboratively contribute to human autoimmune diseases.

Hepatopulmonary syndrome is an uncommon complication of nonacute liver failure, and in rare cases, hypoxia may be the presenting sign of liver dysfunction. The condition, once thought to be a contraindication, is improved in most cases by transplantation. There is a significant risk of postoperative, hypoxia-related morbidity and mortality in patients with hepatopulmonary syndrome. We present a case of life-threatening hypoxia following liver transplantation for liver failure and associated hepatopulmonary syndrome, with successful management using extracorporeal membrane oxygenation.

BACKGROUND: The cyclin-dependent kinase (cdk) inhibitor p21 inhibits cellular proliferation of many cell types, including T cells. Autoimmune models, however, have yielded conflicting results regarding the role of cdk inhibitors and T-cell function. The role of p21 in T-cell function after transplantation has not been investigated directly. We hypothesized that p21 plays an important role in alloantigen-driven responses in vitro in mixed lymphocyte cultures (MLC) and in vivo using the heterotopic murine cardiac allograft model. METHODS: Wild type (WT) and p21-deficient (p21-/-) mice were used as recipients, and the effects of p21 overexpression were assessed by transplanting p21 adenoviral-transfected cardiac allografts. Enzyme-linked immunospot (ELISPOT) and 3H-thymidine incorporation were used to evaluate for T-cell priming and proliferation in vitro, whereas graft histology was evaluated for rejection. RESULTS: When stimulated with alloantigens in vitro, splenocytes from p21-/- mice mounted enhanced proliferative responses and decreased Th2 responses relative to their WT counterparts. No differences in Th1 responses were noted when p21-/- cells were stimulated with alloantigens in vitro; however, after cardiac transplantation, Th1 responses were enhanced in p21-/- recipients relative to WT mice. This enhanced in vivo Th1 response was associated with exacerbated graft rejection in p21-/- recipients. Interestingly, p21 transfection of WT allografts inhibited graft rejection and Th1 priming. CONCLUSIONS: p21 controls the intensity of the immune response posttransplantation, with overexpression inhibiting allograft rejection. Our data demonstrate that p21 controls T-cell priming and suggest that p21 and other cdk inhibitors may serve as potential targets for therapeutic manipulation of alloimmune responses.