Promotion of allograft survival by CD4+CD25+ regulatory T cells: evidence for in vivo inhibition of effector cell proliferation.

Regulatory T cells preserve tolerance to peripheral self-Ags and may control the response to allogeneic tissues to promote transplantation tolerance. Although prior studies have demonstrated prolonged allograft survival in the presence of regulatory T cells (T-reg), data documenting the capacity of these cells to promote tolerance in immunocompetent transplant models are lacking, and the mechanism of suppression in vivo remains unclear. We used a TCR transgenic model of allograft rejection to characterize the in vivo activity of CD4(+)CD25(+) T-reg. We demonstrate that graft Ag-specific T-reg effectively intercede in the rejection response of naive T cells to established skin allografts. Furthermore, CFSE labeling demonstrates impaired proliferation of naive graft Ag-specific T cells in the draining lymph node in the presence of T-reg. These results confirm the efficacy of T-reg in promoting graft survival and suggest that their suppressive action is accomplished in part through inhibition of proliferation.

Vulnerability of allografts to rejection by MHC class II-restricted T-cell receptor transgenic mice.

BACKGROUND: Examination of the in vivo activation and function of CD4+ T cells in response to allografts may advance our understanding of the rejection process. We analyzed the capacity of transgenic class II-restricted CD4 T cells to reject skin, cardiac, and islet transplants. METHODS: TS1 mice possess a high frequency of CD4+ T cells specific for the immunodominant epitope of the viral hemagglutinin (HA) protein. We analyzed the kinetics of rejection of skin, heart, and islet grafts by naïve and sensitized TS1 mice and by adoptively transferred TS1 lymphocytes. RESULTS: Rejection of heart transplants was more rapid than skin grafts (mean survival time, 12.9 vs. 26.6 days), and islet grafts survived indefinitely in TS1 mice. These findings may be partly attributable to the supranormal frequency of HA-reactive cells in TS1 mice. In support of this, we found that adoptive transfer of 5 x 10(5) TS1 lymphocytes to Balb/c hosts effected consistent rejection of HA-bearing skin transplants, whereas a significantly greater number (3 x 10(6)) was required for heart transplant rejection. The in vivo proliferative response of HA-specific T cells to heart and skin was found to be robust and predominantly localized to the draining lymph nodes. CONCLUSION: We developed a model of allograft rejection in which the responding T cells and relevant graft antigen are specifically defined. Adoptive transfer of carboxy-fluorescein succinimidyl ester-labeled transgenic T cells allowed us to visualize a robust proliferative response in vivo to heart and skin allografts, which in both cases was localized to regional lymph nodes.

CD25+ immunoregulatory CD4 T cells mediate acquired central transplantation tolerance.

Transplantation tolerance is induced reliably in experimental animals following intrathymic inoculation with the relevant donor strain Ags; however, the immunological mechanisms responsible for the induction and maintenance of the tolerant state remain unknown. We investigated these mechanisms using TCR transgenic mice (TS1) that carry T cells specific for an immunodominant, MHC class II-restricted peptide (S1) of the influenza PR8 hemagglutinin (HA) molecule. We demonstrated that TS1 mice reject skin grafts that have transgene-encoded HA molecules (HA104) as their sole antigenic disparity and that intrathymic but not i.v. inoculation of TS1 mice with S1 peptide induces tolerance to HA-expressing skin grafts. Intrathymic peptide inoculation was associated with a dose-dependent reduction in T cells bearing high levels of TCR specific for HA. However, this reduction was both incomplete and transient, with a full recovery of S1-specific thymocytes by 4 wk. Peptide inoculation into the thymus also resulted in the generation of immunoregulatory T cells (CD4+CD25+) that migrated to the peripheral lymphoid organs. Adoptive transfer experiments using FACS sorted CD4+CD25- and CD4+CD25+ T cells from tolerant mice revealed that the former but not the latter maintain the capacity to induce rejection of HA bearing skin allografts in syngeneic hosts. Our results suggest that both clonal frequency reduction in the thymus and immunoregulatory T cells exported from the thymus are critical to transplantation tolerance induced by intrathymic Ag inoculation.

Inferior vena cava filters in malignant disease.

PURPOSE: Patients undergoing treatment for cancer have a high risk and prevalence of venous thrombosis and frequent contraindications to anticoagulation therapy that lead to placement of caval filters. We questioned whether the increasing frequency of this intervention has clinical benefit. METHODS: Between 1993 and 2000, 116 patients undergoing active treatment for malignant disease underwent filter placement at our institution. Outcome was retrospectively assessed with regard to procedural complications, recurrent thrombotic events, and patient survival. RESULTS: Primary tumors were gastrointestinal (n = 25), lung (n = 24), breast (n = 14), gynecologic (n = 14), prostate (n = 12), hematologic (n = 8), urologic (n = 4) or other (n = 15). Indications for filter were contraindication to anticoagulation therapy for deep venous thrombosis (DVT) or pulmonary embolism (PE; bleeding, n = 33; surgery, n = 29), recurrent or propagating DVT or recurrent PE during anticoagulation therapy (n = 17), right heart failure (n = 15), intracerebral malignancy (n = 7), and other indications (n = 18). Procedural complications were five localized hematomas, none necessitating surgery. Two patients had progressive DVT and three had clinical recurrent PE after filter placement. Life-table analysis revealed survival rates of 68.8% at 30 days, 49.4% at 3 months, and 26.8% at 1 year (standard error, <5%). Of 91 patients with stage IV disease, 42 patients had died of cancer within 6 weeks and only 13.7% were alive at 1 year. CONCLUSION: Although recurrent thromboembolic events are rare after caval filter placement in patients with malignant disease, survival is short in most patients with stage IV disease and prevention of PE may be of little clinical benefit and a poor utilization of resources. Oncologists should consider these sobering results when requesting filter placement in patients with advanced malignant disease.