The Role of Direct Presentation by Donor Dendritic Cells in Rejection of Minor Histocompatibility Antigen-Mismatched Skin and Hematopoietic Cell Grafts

Background. The success of transplantation is hampered by rejection of the graft by alloreactive T cells. Donor dendritic cells (DC) have been shown to be required for direct priming of immune responses to antigens from major histocompatibility complex-mismatched grafts. However, for immune responses to major histocompatibility complex-matched, minor histocompatibility (H) antigen mismatched grafts, the magnitude of the T-cell response to directly presented antigens is reduced, and the indirect pathway is more important. Therefore, we aimed to investigate the requirement for donor DC to directly present antigen from minor H antigen mismatched skin and hematopoietic grafts.Methods. Langerhans cell-or conventional (c) DC-depleted skin or hematopoietic cells from male DC-specific diphtheria toxin receptor mice were grafted onto, or injected into, syngeneic female recipients, and survival of the male tissue was compared with nondepleted tissue. Activation of the alloreactive immune response was tracked by the expansion of T cells specific for male HY-derived epitopes.Results. Our data demonstrate that depletion of donor Langerhans cell, dermal cDC, or both from skin grafts prolongs their survival but does not prevent rejection. Extended survival correlates with delayed expansion of HY peptide-specific CD8(+) T cells. In addition, depletion of donor cDC delays rejection of male hematopoietic cells.Conclusions. Our results demonstrate for the first time that direct presentation of minor H antigens by donor DC is required for efficient rejection of skin and hematopoietic grafts by CD8(+) T cells. But, in the absence of donor DC, indirect presentation of minor antigens is sufficient to mediate the response

Evaluating the Potential Effectiveness of Compensatory Mitigation Strategies for Marine Bycatch

Conservationists are continually seeking new strategies to reverse population declines and safeguard against species extinctions. Here we evaluate the potential efficacy of a recently proposed approach to offset a major anthropogenic threat to many marine vertebrates: incidental bycatch in commercial fisheries operations. This new approach, compensatory mitigation for marine bycatch (CMMB), is conceived as a way to replace or reduce mandated restrictions on fishing activities with compensatory activities (e.g., removal of introduced predators from islands) funded by levies placed on fishers. While efforts are underway to bring CMMB into policy discussions, to date there has not been a detailed evaluation of CMMB's potential as a conservation tool, and in particular, a list of necessary and sufficient criteria that CMMB must meet to be an effective conservation strategy. Here we present a list of criteria to assess CMMB that are tied to critical ecological aspects of the species targeted for conservation, the range of possible mitigation activities, and the multi-species impact of fisheries bycatch. We conclude that, overall, CMMB has little potential for benefit and a substantial potential for harm if implemented to solve most fisheries bycatch problems. In particular, CMMB is likely to be effective only when applied to short-lived and highly-fecund species (not the characteristics of most bycatch-impacted species) and to fisheries that take few non-target species, and especially few non-seabird species (not the characteristics of most fisheries). Thus, CMMB appears to have limited application and should only be implemented after rigorous appraisal on a case-specific basis; otherwise it has the potential to accelerate declines of marine species currently threatened by fisheries bycatch

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.Journal ArticleMulticenter StudyRandomized Controlled TrialResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event