Contribution of regulatory T cells and effector T cell deletion in tolerance induction by costimulation blockade.

Blocking of costimulatory signals for T cell activation leads to tolerance in several transplantation models, but the underlying mechanisms are incompletely understood. We analyzed the involvement of regulatory T cells (Treg) and deletion of alloreactive cells in the induction and maintenance of tolerance after costimulation blockade in a mouse model of graft-vs-host reaction. Injection of splenocytes from the C57BL/6 parent strain into a sublethally irradiated F(1) offspring (C57BL/6 x C3H) induced a GVHR characterized by severe pancytopenia. Treatment with anti-CD40L mAb and CTLA4-Ig every 3 days during 3 wk after splenocyte injection prevented disease development and induced a long-lasting state of stable mixed chimerism (>120 days). In parallel, host-specific tolerance was achieved as demonstrated by lack of host-directed alloreactivity of donor-type T cells in vitro and in vivo. Chimerism and tolerance were also obtained after CD25(+) cell-depleted splenocyte transfer, showing that CD25(+) natural Treg are not essential for tolerance induction. We further show that costimulation blockade results in enhanced Treg cell activity at early time points (days 6-30) after splenocyte transfer. This was demonstrated by the presence of a high percentage of Foxp3(+) cells among donor CD4(+) cells in the spleen of treated animals, and our finding that isolated donor-type T cells at an early time point (day 30) after splenocyte transfer displayed suppressive capacity in vitro. At later time points (>30 days after splenocyte transfer), clonal deletion of host-reactive T cells was found to be a major mechanism responsible for tolerance.

Human T cell activation by costimulatory signal-deficient allogeneic cells induces inducible costimulator-expressing anergic T cells with regulatory cell activity.

Although immunoregulation by several types of regulatory T cells is now clearly established in mice, the demonstration of such regulatory T cells in humans has been proven more difficult. In this study we demonstrate the induction of anergic regulatory T cells during an MLR performed in the presence of blocking mAb to the costimulatory molecules CD40, CD80, and CD86. Despite this costimulation blockade, which totally blocks T cell proliferation and cytokine production, a nonproliferating T cell subpopulation was activated to express inducible costimulator (ICOS). These ICOS(+) cells were anergic when restimulated with unmanipulated allogeneic stimulator cells at the level of proliferation and Th1 and Th2 cytokine production, but they did produce IL-10. These ICOS-expressing cells also blocked the capacity of reciprocal ICOS-negative cells to proliferate and to produce cytokines. ICOS(+) anergic cells could suppress allogenic responses of either primed or naive T cells through inhibition of IL-2 gene transcription. Suppression was not mediated by IL-10 and did not require ICOS-ICOS ligand interaction, but depended on cell-cell contact. Thus, a subtype of regulatory T cells in human blood can be activated in the absence of costimulatory signals from CD40, CD80, and CD86, and they can be identified by expression of ICOS after activation.

New technology for improved storm risk assessment in the Caribbean

The effects of tropical storms on caribbean island satates are reviewed and their potential for destruction from coastal flloding and extreme winds are highlighted in the context of sea-level rise and increasingly dense coastal development. the Caribbean disaster mitigation project (CDMP) is applying new tecnology in modelling these effects. The model used by CDMP relies on a generic dabase structure using available 'off the shelf' data sources such as satellite imagery and the National Hurricane Center dabase.The model provides probable maximun values for wind at surface and for still-water elevation and wave height at the coastline.Applications in the areas of land use planning design of coastal works and disaster preparedness are presented. The results of this model compare favourably to those of existing storm surge models such as the WHAFIS model of the Federal Emergency Management Agency (FEMA) and the SLOSH model of the National Oceanographic and Atmospheric Agency (NOAA) (AU)

Natural disasters : Linking economics and the environment with a vengeance

An often overlooked aspect in the linkage between economic development and environment is the vulnerability of development to environmental extremes, or natural hazards. The impact of a natural disaster on the economy of a small developing country can be devasting. Jamaica's GDP for calendar 1988 fell by 2

as against an expected growth of 5

. Settlements and their services, basic infrastructure, productive facilities, and even the natural resource base can sustain severe damage, forcing the country to divert scarce funds to their rehabilitation. The foreign exchange earning capacity of export agriculture and tourism can be wiped out for a substantial period, at a time when the country needs to acquire goods and sevices from abroad as inputs for the rehabilitation effort. Countries in the region, and their international development assistance agencies continue to formulate development plans and investment projects without due consideration to the risks posed by natural hazards. Yet the recent disasters that affected the region serve as a reminder that sustainable development cannot be attained without mitigating hazard risk perception and response. Significant progress can be made towards this end by including hazard assessment and vulnerability analysis in the development planning process, and by expanding the project appraisal process to include a cost-benefit analysis for investment in appropriate loss reduction and mitigation measures