Erosion of Transplantation Tolerance After Infection.

Recent clinical studies suggest that operational allograft tolerance can be persistent, but long-term surviving allografts can be rejected in a subset of patients, sometimes after episodes of infection. In this study, we examined the impact of Listeria monocytogenes (Lm) infection on the quality of tolerance in a mouse model of heart allograft transplantation. Lm infection induced full rejection in 40% of tolerant recipients, with the remaining experiencing a rejection crisis or no palpable change in their allografts. In the surviving allografts on day 8 postinfection, graft-infiltrating cell numbers increased and exhibited a loss in the tolerance gene signature. By day 30 postinfection, the tolerance signature was broadly restored, but with a discernible reduction in the expression of a subset of 234 genes that marked tolerance and was down-regulated at day 8 post-Lm infection. We further demonstrated that the tolerant state after Lm infection was functionally eroded, as rejection of the long-term surviving graft was induced with anti-PD-L1 whereas the same treatment had no effect in noninfected tolerant mice. Collectively, these observations demonstrate that tolerance, even if initially robust, exists as a continuum that can be eroded following bystander immune responses that accompany certain infections.

Adoptive Transfer of Tracer-Alloreactive CD4+ T Cell Receptor Transgenic T Cells Alters the Endogenous Immune Response to an Allograft.

T cell receptor transgenic (TCR-Tg) T cells are often used as tracer populations of antigen-specific responses to extrapolate findings to endogenous T cells. The extent to which TCR-Tg T cells behave purely as tracer cells or modify the endogenous immune response is not clear. To test the impact of TCR-Tg T cell transfer on endogenous alloimmunity, recipient mice were seeded with CD4+ or CD8+ TCR-Tg or polyclonal T cells at the time of cardiac allograft transplantation. Only CD4+ TCR-Tg T cells accelerated rejection and, unexpectedly, led to a dose-dependent decrease in both transferred and endogenous T cells infiltrating the graft. In contrast, recipients of CD4+ TCR-Tg T cells exhibited enhanced endogenous donor-specific CD8+ T cell activation in the spleen and accelerated alloantibody production. Introduction of CD4+ TCR-Tg T cells also perturbed the intragraft accumulation of innate cell populations. Transferred CD4+ TCR-Tg T cells alter many aspects of endogenous alloimmunity, suggesting that caution should be used when interpreting experiments using these adoptively transferred cells because the overall nature of allograft rejection may be altered. These results also may have implications for adoptive CD4+ T cell immunotherapy in tumor and infectious clinical settings because cell infusion may have additional effects on natural immune responses.

Tracking of TCR-Transgenic T Cells Reveals That Multiple Mechanisms Maintain Cardiac Transplant Tolerance in Mice.

Solid organ transplantation tolerance can be achieved following select transient immunosuppressive regimens that result in long-lasting restraint of alloimmunity without affecting responses to other antigens. Transplantation tolerance has been observed in animal models following costimulation or coreceptor blockade therapies, and in a subset of patients through induction protocols that include donor bone marrow transplantation, or following withdrawal of immunosuppression. Previous data from our lab and others have shown that proinflammatory interventions that successfully prevent the induction of transplantation tolerance in mice often fail to break tolerance once it has been stably established. This suggests that established tolerance acquires resilience to proinflammatory insults, and prompted us to investigate the mechanisms that maintain a stable state of robust tolerance. Our results demonstrate that only a triple intervention of depleting CD25+ regulatory T cells (Tregs), blocking programmed death ligand-1 (PD-L1) signals, and transferring low numbers of alloreactive T cells was sufficient to break established tolerance. We infer from these observations that Tregs and PD-1/PD-L1 signals cooperate to preserve a low alloreactive T cell frequency to maintain tolerance. Thus, therapeutic protocols designed to induce multiple parallel mechanisms of peripheral tolerance may be necessary to achieve robust transplantation tolerance capable of maintaining one allograft for life in the clinic.

A modified approach to the phenol and alcohol chemical partial matrixectomy.

The phenol and alcohol matrixectomy is a frequently used technique for treating onychocryptosis in healthy patients. This article describes a modification of this common procedure. The modified version provides a quick and easy method of removing an ingrown nail.

Treatment of anxiety: a comparison of the usefulness of self-hypnosis and a meditational relaxation technique. An overview.

We have investigated prospectively the efficacy of two nonpharmacologic relaxation techniques in the therapy of anxiety. A simple, meditational relaxation technique (MT) that elicits the changes of decreased sympathetic nervous system activity was compared to a self-hypnosis technique (HT) in which relaxation, with or without altered perceptions, was suggested. 32 patients with anxiety neurosis were divided into 2 groups on the basis of their responsivity to hypnosis: moderate-high and low responsivity. The MT or HT was then randomly assigned separately to each member of the two responsivity groups. Thus, 4 treatment groups were studied: moderate-high responsivity MT; low responsivity MT; moderate-high responsivity HT; and low responsivity HT. The low responsivity HT group, by definition largely incapable of achieving the altered perceptions essential to hypnosis, was designed as the control group. Patients were instructed to practice the assigned technique daily for 8 weeks. Change in anxiety was determined by three types of evaluation: psychiatric assessment; physiologic testing; and self-assessment. There was essentially no difference between the two techniques in therapeutic efficacy according to these evaluations. Psychiatric assessment revealed overall improvement in 34% of the patients and the self-rating assessment indicated improvement in 63% of the population. Patients who had moderate-high hypnotic responsivity, independent of the technique used, significantly improved on psychiatric assessment (p = 0.05) and decreased average systolic blood pressure from 126.1 to 122.5 mm Hg over the 8-week period (p = 0.048). The responsivity scores at the higher end of the hypnotic responsivity spectrum were proportionately correlated to greater decreases in systolic blood pressure (p = 0.075) and to improvement by psychiatric assessment (p = 0.003). There was, however, no consistent relation between hypnotic responsivity and the other assessments made, such as diastolic blood pressure, oxygen consumption, heart rate and the self-rating questionnaires. The meditational and self-hypnosis techniques employed in this investigation are simple to use and effective in the therapy of anxiety.