Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.
Because of the major difficulties in measuring clinical end points in multiple sclerosis (MS) treatment trials, there has been much enthusiasm for using magnetic resonance imaging (MRI) findings as an alternative outcome. To provide international consensus guidelines for the use of MRI in MS clinical trials, a task force of the US National MS Society was convened. The recommendations of the task force are presented in this review. Given the high sensitivity for detecting pathological activity in relapsing-remitting and secondary progressive MS, monthly T2-weighted and gadolinium-enhanced brain MRI is an excellent tool for short-term exploratory trials of new agents where it serves as the primary end point; in particular, failure to demonstrate a reduction in lesion activity avoids the time, cost, and risks of a larger clinical end point study. However, conventional MRI findings have a limited correlation with disability in established MS. The primary end point of a definitive trial should therefore be clinical, although serial MRI at 6- to 12-month intervals is a useful secondary end point in providing an index of pathological progression. In trials of patients presenting with clinically isolated syndromes suggestive of MS, MRI findings can be used in the entry criteria, and as a secondary outcome measure, but conversion to clinically definite MS should be the primary outcome. The pathological substrates of irreversible disability are demyelination and axonal loss. Putative magnetic resonance markers for these processes include decreased N-acetylaspartate on proton magnetic resonance spectroscopy, decreased magnetization transfer ratios, hypointensity on T1-weighted images, and loss of short T2 water fractions, some of which relate more closely to disability than conventional MRI findings. Further technical developments should lead to more accurate quantitation, greater pathological specificity, and stronger clinical correlations.
IntroductionBone marrow and organ transplantation are curative for an increasing number of diseases. The major barriers are graft-versushost disease (GVHD) and rejection, which currently are inhibited by toxic nonspecific immunosuppression. Induction of donorspecific tolerance without the requirement for immunosuppressive drugs would be highly desirable. Adoptive therapy with ex vivo-induced antigen (Ag)-specific T regulatory cells (Tregs) has considerable potential.CD4 ϩ CD25 high Foxp3 ϩ T cells are potent regulators of transplantation rejection 1-5 and GVHD. [6][7][8] Natural Tregs are produced as a separate lineage in the thymus that constitute 2% to 10% of peripheral CD4 ϩ T cells, 9 inhibit in a non-Ag-specific manner, and protect normal tissue from immune injury. 2,10 The CD4 ϩ CD25 ϩ T cells that mediate transplantation tolerance are Ag-specific, 1-4 but how they develop and differ to natural non-Ag-specific CD4 ϩ CD25 ϩ Tregs is poorly understood. 9 In fully allogeneic models, naive CD4 ϩ CD25 high T cells, if given at a ratio of 1:1 with naive CD4 ϩ T cells, can totally prevent rejection 5 and GVHD 7 but only partially block GVHD at a ratio of 1:2. 8 At a ratio of 1:10, naive CD4 ϩ CD25 high T cells do not block rejection 5 or GVHD. 7 Given the very low number of CD4 ϩ CD25 ϩ T cells in the T-cell population, it is impractical to prepare enough cells for therapeutic usage at a ratio of 1:1. Ex vivo polyclonal activation of CD4 ϩ CD25 ϩ T cells with interleukin-2 (IL-2) and anti-CD3 monoclonal antibody (mAb) 6 or IL-2, anti-CD3 and anti-CD28 11 results in 200-to 250-fold cell number expansion but no enhanced Ag-specific regulatory capacity. 12 Culture of CD4 ϩ CD25 ϩ Tregs with allo-Ag and IL-2 for a week or more also increases cell numbers but does not induce high potency Agspecific CD4 ϩ CD25 ϩ Tregs, in that a ratio of 2:1 13 or 5:1 14 with naive T cells is required to suppress skin graft rejection. Similarly, in GVHD, a 7:10 ratio of IL-2-and allo-Ag-cultured Tregs to naive cells is less effective than fresh naive CD4 ϩ CD25 ϩ T cells, in that they delay but do not fully prevent GVHD. 8 In contrast, CD4 ϩ CD25 ϩ T cells within CD4 ϩ T cells from hosts with allo-Ag-specific tolerance to a graft can transfer allo-Ag-specific tolerance at an effective ratio of less than 1:20. 2,3 These tolerant CD4 ϩ T cells, when cultured in vitro, lose the capacity to transfer tolerance unless stimulated by specific donor Ag in media supplemented with T-cell cytokines. 2,15,16 Which cytokines are most effective at maintaining specific Tregs is unknown, but IL-2 alone is insufficient. 16 This suggests that Ag-specific CD4 ϩ CD25 ϩ T cells may become dependent on cytokines other than IL-2. We have identified that interferon-␥ (IFN-␥) and IL-5, but not other T-helper 1 (Th1) and Th2 cytokines, promoted proliferation and survival of Agspecific tolerance mediating Tregs from rats tolerant to an allograft (B.M.H., M.N., K.M.P., N.D.V., G.T.T., S.J.H., unpublished data). 20 we examined whether Th1 and Th2 cytokines promote...
This study suggests that in active multiple sclerosis during treatment with injectable disease-modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short-term disability burden.
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