The efficacy of add-on tacrolimus for minor flare in patients with systemic lupus erythematosus: a retrospective study.

OBJECTIVE: We have assessed the effectiveness of tacrolimus for minor flares in systemic lupus erythematosus (SLE) patients. METHODS: The medical records of 313 patients were retrospectively reviewed over a period of seven years, from 2006 to 2013. We enrolled patients with minor flare treated with add-on tacrolimus, without glucocorticoid (GC) intensification (tacrolimus group). Minor flare was defined as a ≥ 1-point increase in a total score between 3 and 11 in the SLE Disease Activity Index (SLEDAI). We enrolled as controls patients who were administered increased doses of GC for minor flare (GC group). All patients were followed for one year. The primary outcome measure was the proportion of responders. RESULTS: There were 14 eligible patients in the tacrolimus group and 20 eligible patients in the GC group. The mean SLEDAI at flare tended to be higher in the tacrolimus group than in the GC group (7.5 vs. 6.2, p = 0.085). A mean dose of 1.6 mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7 mg/day in the GC group. The proportion of responders was 86% (12/14) in the tacrolimus group and 75% (15/20) in the GC group (p = 0.67). The mean dose of GC at 12 months was higher in the GC group than in the tacrolimus group (9.7 mg/day vs. 7.1 mg/day, p < 0.05). Only one patient discontinued tacrolimus because of fatigue after three months. CONCLUSION: Adding tacrolimus without increasing the GC dose may provide an effective treatment option for minor flares in patients with SLE.

Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents recognition of transgene products by CD8(+) cytotoxic T lymphocytes.

The in vivo persistence of gene-modified cells may be limited by the development of a host immune response to vector-encoded proteins. Herpesviruses evade cytotoxic T-lymphocyte (CTL) recognition by expressing genes which interfere selectively with presentation of viral antigens by class I major histocompatibility complex (MHC) molecules. Here, we studied the use of retroviral vectors encoding herpes simplex virus ICP47, human cytomegalovirus (HCMV) US3, or HCMV US11 to decrease presentation of viral proteins and transgene products to CD8(+) CTL. Human fibroblasts and T cells transduced to express the ICP47, US3, or US11 genes alone exhibited a decrease in cell surface class I MHC expression. The combination of ICP47 and US11 rendered fibroblasts negative for surface class I MHC and allowed a class I MHC-low population of T cells to be sorted by flow cytometry. Fibroblasts and T cells expressing both ICP47 and US11 were protected from CTL-mediated lysis and failed to stimulate specific memory T-cell responses to transgene products in vitro. Our findings suggest that expression of immunoregulatory viral gene products could be a potential strategy to prolong transgene expression in vivo.

The misdiagnosis of delirium.

The authors examined the ability of nonpsychiatric house staff to accurately diagnose delirium at the time of consultation. Of 221 consultations over a 5-year period, 46% were misdiagnosed by the house staff. House staff on the general medicine wards and the nonintensive care unit environment did significantly better than those on the surgical wards and intensive care units. Age, gender, and race of the patient did not overall influence incorrect diagnoses; however, when a misdiagnosis occurred, women were more often given a diagnosis of a depressive disorder, whereas men were more often given a "no diagnosis" label. Finally, the consultees improved over an academic year in accurately identifying women as delirious, whereas no such learning curve existed for men.

Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor.

BACKGROUND: Cytomegalovirus (CMV) disease in immunocompromised patients correlates with a deficiency of CD8+ cytotoxic T lymphocytes specific for CMV. We evaluated the safety and immunologic effects of immunotherapy with clones of these lymphocytes in recipients of allogeneic bone marrow transplants. METHODS: Clones of CD8+ cytotoxic T cells specific for CMV proteins were isolated from the blood of bone marrow donors. Fourteen patients each received four intravenous infusions of these clones from their donors beginning 30 to 40 days after marrow transplantation. The reconstitution of cellular immunity against CMV was monitored before and during the period of infusions and for up to 12 weeks after the final infusion. The rearranged genes encoding the T-cell receptor served as markers in evaluating the persistence of the transferred T cells. RESULTS: No toxic effects related to the infusions were observed. Cytotoxic T cells specific for CMV were reconstituted in all patients. In vitro measurements showed that cytotoxic activity against CMV was significantly increased (P < 0.001) after the infusions in 11 patients who were deficient in such activity before therapy. The level of activity achieved after the infusions was similar to that measured in the donors. Analysis of rearranged T-cell-receptor genes in T cells obtained from two recipients indicated that the transferred clones persisted for at least 12 weeks. Cytotoxic-T-cell activity declined in patients deficient in CD4+ T-helper cells specific for CMV, suggesting that helper-T-cell function is needed for the persistence of transferred CD8+ T cells. Neither CMV viremia nor CMV disease developed in any of the 14 patients. CONCLUSIONS: The transfer of CMV-specific clones of CD8+ T cells derived from the bone marrow donor is a safe and effective way to reconstitute cellular immunity against CMV after allogeneic marrow transplantation.

Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones.

The adoptive transfer of antigen-specific T cells to establish immunity is an effective therapy for viral infections and tumors in animal models. The application of this approach to human disease would require the isolation and in vitro expansion of human antigen-specific T cells and evidence that such T cells persist and function in vivo after transfer. Cytomegalovirus-specific CD8+ cytotoxic T cell (CTL) clones could be isolated from bone marrow donors, propagated in vitro, and adoptively transferred to immunodeficient bone marrow transplant recipients. No toxicity developed and the clones provided persistent reconstitution of CD8+ cytomegalovirus-specific CTL responses.