People are neglected, not diseases: the relationship between disability and neglected tropical diseases.

People with disabilities and the neglected tropical diseases (NTDs) are separately receiving increased focus. In light of this positive development, and the similarities and intersections between the negative impacts experienced by both people with disabilities and people with NTDs, we believe now is the right time to focus attention on the overlap between the two. Both people with NTDs and people with disabilities experience a myriad of overlapping negative health, financial and socio-cultural consequences. Despite this, we believe that disability is not yet properly prioritised on the development agenda, and that there are multiple opportunities to make NTD programming more inclusive, to the benefit of those at this neglected intersection and beyond. There are both opportunities and need to scale up, integrate, and invest in inclusive, health system-focused NTD programming. Realisation of the Sustainable Development Goals, Universal Health Coverage, and the control and elimination of NTDs all rely on ensuring people with disabilities are not left behind.

Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis.

Autologous haematopoietic stem cell transplantation has been tried as one experimental strategy for the treatment of patients with aggressive multiple sclerosis refractory to other immunotherapies. The procedure is aimed at ablating and repopulating the immune repertoire by sequentially mobilizing and harvesting haematopoietic stem cells, administering an immunosuppressive conditioning regimen, and re-infusing the autologous haematopoietic cell product. 'Non-myeloablative' conditioning regimens to achieve lymphocytic ablation without marrow suppression have been proposed to improve safety and tolerability. One trial with non-myeloablative autologous haematopoietic stem cell transplantation reported clinical improvement and inflammatory stabilization in treated patients with highly active multiple sclerosis. The aim of the present study was to understand the changes in the reconstituted immune repertoire bearing potential relevance to its mode of action. Peripheral blood was obtained from 12 patients with multiple sclerosis participating in the aforementioned trial and longitudinally followed for 2 years. We examined the phenotype and function of peripheral blood lymphocytes by cell surface or intracellular staining and multi-colour fluorescence activated cell sorting alone or in combination with proliferation assays. During immune reconstitution post-transplantation we observed significant though transient increases in the proportion of CD4+ FoxP3+ T cells and CD56(high) natural killer cell subsets, which are cell subsets associated with immunoregulatory function. CD8+ CD57+ cytotoxic T cells were persistently increased after therapy and were able to suppress CD4+ T cell proliferation with variable potency. In contrast, a CD161(high) proinflammatory CD8+ T cell subset was depleted at all time-points post-transplantation. Phenotypic characterization revealed that the CD161(high)CD8+ T cells were mucosal-associated invariant T cells, a novel cell population originating in the gut mucosa but expressing the central nervous system-homing receptor CCR6. Detection of mucosal-associated invariant T cells in post-mortem multiple sclerosis brain white matter active lesions confirmed their involvement in the disease pathology. Intracellular cytokine staining demonstrated interferon γ and interleukin 17 production and lack of interleukin 10 production, a pro-inflammatory profile. Mucosal-associated invariant T cell frequency did not change in patients treated with interferon ß; and was more depleted after autologous haematopoietic stem cell transplantation than in patients who had received high-dose cyclophosphamide (n = 7) or alemtuzumab (n = 21) treatment alone, suggesting an additive or synergistic effect of the conditioning regime components. We propose that a favourably modified balance of regulatory and pro-inflammatory lymphocytes underlies the suppression of central nervous system inflammation in patients with multiple sclerosis following non-myeloablative autologous haematopoietic stem cell transplantation with a conditioning regimen consisting of cyclophosphamide and alemtuzumab.

Human platelet antigen 1a epitopes are dependent on the cation-regulated conformation of integrin α(IIb)ß(3) (GPIIb/IIIa).

BACKGROUND: The HPA-1a (Leu(33)) polymorphism of platelet integrin αIIbß3 is the target of alloantibodies in 70-80% cases of neonatal alloimmune thrombocytopenia (NAIT) in Caucasians and reliable detection of these antibodies is essential for appropriate clinical management. However, the ability to detect such antibodies is highly variable between laboratories and, in a number of clinical cases where there is a HPA-1 genotype mismatch between mother and neonate, HPA-1a antibodies are undetectable. Furthermore, some studies have not shown a consistent relationship between maternal anti-HPA-1a level and neonatal platelet count. Since the integrity and conformation of the αIIbß3 complex are dependent on divalent cations, we investigated whether HPA-1a epitope integrity and/or conformation might be affected by the presence of the cation chelator EDTA in patient samples or in assay buffers, thus providing a possible explanation for the variable sensitivity of current assays. PRINCIPLE FINDINGS: Exposure of the αIIbß3 complex to EDTA resulted in reduced reactivity of three anti-HPA-1a mAbs (B2, 19-7 and 23-15). More significantly, cation chelation adversely affected detection of polyclonal anti-HPA-1a, not only in the platelet immunofluorescence assay, where alloantibody binding was reduced compared to control platelets (mean MFI reduction 44.5%, range 17.3-69.7%, n=4), but also in the commonly used monoclonal antibody specific immobilisation of platelet antigens assay (MAIPA) where both alloantibody and monoclonal capture antibody binding were reduced (mean OD reduction 82.8%, range 68.3-96.6%, n=9). CONCLUSIONS: These data show that HPA-1a antibodies recognise epitopes on αIIbß3 that are sensitive to EDTA treatment and that cation chelation grossly reduces the sensitivity of the MAIPA assay by diminishing not only HPA-1a alloantibody binding but also 'capture' monoclonal antibody binding. These findings may, in part, explain the current variability in antibody measurement and will guide the development of more sensitive tests for anti-integrin antibodies in NAIT and other conditions.

Resetting autoimmunity in the nervous system: The role of hematopoietic stem cell transplantation.

According to current concepts for multiple sclerosis (MS), a fundamental pathogenic role is played by T- and B-cells that inappropriately recognize self antigens and initiate a cell-mediated or humoral inflammatory reaction that injures myelin and axons, and results in neural dysfunction and loss. Transplantation of bone marrow-derived hematopoietic stem cells following high-dose immunosuppression is being evaluated as an experimental treatment for severe forms of immune-mediated disorders, including MS. The primary goal of this therapeutic approach is to induce medication-free remission from new disease activity by correcting the immune aberrations that promote the attack against self tissue; this approach is termed 'immune repair'. In this review, the clinical experience gained from the use of autologous hematopoietic stem cell transplantation in treating severe forms of MS are presented, and the current understanding of the mechanisms underlying the mode of action of this treatment, including depletion of disease-mediating immune cells, rejuvenation of the immune repertoire and improvement of regulatory cell function, is discussed.

Immune re-education following autologous hematopoietic stem cell transplantation.

The encounter with different environmental antigens during immune maturation from childhood through early adulthood could play a role in the development of autoimmune disease in individuals with a susceptible genetic background. Autologous haematopoietic stem cell transplantation (HSCT) is an experimental treatment for autoimmunity that could offer a second possibility to correct for an aberrant immune reactivity. The premise is that eradication of the existing and pathogenic immune repertoire, in combination with the reinfusion of precursor cells, could reset the immunological clock to an earlier, latent phase of disease. Re-education of the adaptive immune system would occur during the reconstitution of cells under extreme lymphopenia, in which the antigenic priming takes place with a different sequence and timing than during the previous immunological history of the individual, resulting in a different immune repertoire. In this article, we discuss different mechanisms that could contribute to the development of tolerance during immune re-education and address the role of immune renewal and the qualitative reshaping of immunological memory.