Can regulatory T cells improve outcomes of sensitised patients after HLA-Ab incompatible renal transplantation: study protocol for the Phase IIa GAMECHANgER-1 trial.

BACKGROUND: Kidney transplantation is the gold-standard treatment for patients with kidney failure. However, one-third of patients awaiting a kidney transplant are highly sensitized to human leukocyte antigens (HLA), resulting in an increased waiting time for a suitable kidney, more acute and chronic rejection, and a shorter graft survival compared to non-highly sensitised patients. Current standard immunosuppression protocols do not adequately suppress memory responses, and so alternative strategies are needed. Autologous polyclonally expanded regulatory T cells (Tregs) have been demonstrated to be safe in transplant settings and could be a potential alternative to modulate memory immune alloresponses. METHODS: The aim of this trial is to determine whether adoptive transfer of autologous Tregs into HLA sensitised patients can suppress memory T and B cell responses against specific HLA antigens. This is a two-part, multi-centre, prospective clinical trial, comprising an observational phase (Part 1) aiming to identify patients with unregulated cellular memory responses to HLA (Pure HLA Proteins) followed by an interventional phase (Part 2). The first 9 patients identified as being eligible in Part 1 will undergo baseline immune monitoring for 2 months to inform statistical analysis of the primary endpoint. Part 2 is an adaptive, open labelled trial based on Simon's two-stage design, with 21 patients receiving Good Manufacturing Practice (GMP)-grade polyclonally expanded Tregs to a dose of 5-10 × 106 cells/kg body weight. The primary EP is suppression of in vitro memory responses for 2 months post-infusion. 12 patients will receive treatment in stage 1 of Part 2, and 9 patients will receive treatment in stage 2 of Part 2 if ≥ 50% patients pass the primary EP in stage 1. DISCUSSION: This is a prospective study aiming to identify patients with unregulated cellular memory responses to Pure HLA Proteins and determine baseline variation in these patterns of response. Part 2 will be an adaptive phase IIa clinical trial with 21 patients receiving a single infusion of GMP-grade polyclonally expanded Tregs in two stages. It remains to be demonstrated that modulating memory alloresponses clinically using Treg therapy is achievable. TRIAL REGISTRATION: EudraCT Number: 2021-001,664-23. REC Number: 21/SC/0253. Trial registration number ISRCTN14582152.

Dermatitis de contacto alérgica por regiones anatómicas. Claves diagnósticas / Allergic Contact Dermatitis by Anatomical Regions: Diagnostic Clues

La dermatitis de contacto alérgica (DCA) es una enfermedad frecuente en la práctica clínica diaria, con una prevalencia que ha aumentado en los últimos años. Clínicamente se caracteriza por grados variables de eritema, vesiculación, descamación y liquenificación, signos que también están presentes en otros procesos eccematosos. Las pruebas epicutáneas constituyen la principal herramienta diagnóstica para confirmar una DCA, sin embargo, su correcta interpretación requiere de una correcta correlación entre la anamnesis (historial de exposición) y el examen físico. En este artículo se describen de forma práctica y didáctica los patrones clínicos más frecuentes de DCA dependiendo de su localización. El conocimiento de estos patrones no solo ayudará al clínico en el diagnóstico diferencial, sino que también le permitirá sospechar el posible alérgeno y su forma de aplicación

Allergic contact dermatitis (ACD) is a common disease in daily clinical practice, and its prevalence has increased in recent years. It is characterized clinically by varying degrees of erythema, vesiculation, flaking, and lichenification, though these signs can also be present in other eczematous diseases. Patch testing is the main diagnostic tool to confirm ACD, but its accurate interpretation requires correct correlation with the medical history (details of exposure) and physical examination. We provide a practical and instructive description of the most common clinical patters of ACD depending on the area affected. Knowledge of these patterns will not only help the clinician reach the diagnosis but will suggest possible allergens and forms of contact

Allergic Contact Dermatitis by Anatomical Regions: Diagnostic Clues. / Dermatitis de contacto alérgica por regiones anatómicas. Claves diagnósticas.

Allergic contact dermatitis (ACD) is a common disease in daily clinical practice, and its prevalence has increased in recent years. It is characterized clinically by varying degrees of erythema, vesiculation, flaking, and lichenification, though these signs can also be present in other eczematous diseases. Patch testing is the main diagnostic tool to confirm ACD, but its accurate interpretation requires correct correlation with the medical history (details of exposure) and physical examination. We provide a practical and instructive description of the most common clinical patters of ACD depending on the area affected. Knowledge of these patterns will not only help the clinician reach the diagnosis but will suggest possible allergens and forms of contact.

Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment?

We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell-related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group-namely, the tolerant recipients-were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS-independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross-validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.

Modern renal transplantation: present challenges and future prospects.

Renal transplantation offers patients with end stage renal failure improved survival and quality of life compared with dialysis. Although more transplants are being performed in the UK and elsewhere, the size of the renal transplant waiting list is increasing at a faster rate. Live donor transplantation between antibody compatible and incompatible pairs is one of the short term solutions to this; it may also be a sensible long term strategy since it affords better outcomes. Following successful transplantation, balancing the chronic and often deleterious effects of immunosuppression with chronic immune damage poses the key clinical challenge for transplant physicians today. Research efforts worldwide are focused towards immunological tolerance of transplanted organs with two main questions: first, how can we induce tolerance; and second, how can we test that it is operational? Immunosuppressive protocols vary greatly between transplant units, which may be reflected in differing patient and allograft survival.

Changing practice to improve pain control for renal patients.

Pain is a common symptom described by patients with end-stage kidney disease (ESKD) but remains ineffectively managed. The aim of this audit was to determine what proportion of these patients report pain, then introduce the use of an analgesic ladder adapted specifically for ESKD, and finally re-evaluate the prevalence of pain symptoms, looking for an improvement. A cohort of inpatients on the renal wards of a West London teaching hospital was studied. The number of patients reporting pain and the severity of their pain on a scale of 1-10 were recorded. A considerable number of patients were barred from participating because of a language barrier. Interpreters were introduced, and the phase was repeated. The World Health Organization (WHO) three-step analgesic ladder was adapted for patients with ESKD and introduced to medical staff on the renal wards. The number of patients reporting pain and the severity of their pain were re-recorded. There was a significant reduction in the number of patients reporting pain and the severity of their pain. Pain control in patients with ESKD is improved through the use of an adapted version of the WHO analgesic ladder. Strategies must be in place for effective communication with foreign patients.

Rejection mechanisms in transplantation.

While major improvements have been made in the prevention and treatment of hyperacute and acute transplant rejection, most grafts will succumb to chronic rejection: this reflects the extent of our knowledge of the mechanisms that drive these processes. Clinically, transplant rejection is classified according to timeframe and histology into hyperacute (minutes to hours), acute (days to months) and chronic rejection (months to years). Hyperacute and acute rejection are reasonably well understood and occur by immune mediated events whereas chronic rejection probably has immune and non-immune components. The trigger to cell-mediated rejection is allorecognition, where same-species, non-self antigens are detected by the host immune system. This occurs by two distinct mechanisms, called the direct and indirect pathways. The direct pathway results from the recognition of foreign major histocompatibility molecules, intact, on the surface of donor cells. Indirect allorecognition occurs when donor histocompatibility molecules are internalised, processed, and presented as peptides by host antigen presenting cells. Animal and human studies strongly suggest that acute rejection is predominantly triggered by the direct pathway although if the latter is blocked then the indirect pathway can suffice. Donor antigen presenting cells within the graft become depleted with time and the frequency of T cells reactive to the direct pathway diminishes irrespective of whether or not chronic rejection occurs. This implies that the direct pathway is unlikely to contribute to chronic rejection. Assays of T cell responses have, however, found an association between the indirect pathway and chronic rejection although it is unlikely that this is the whole story: there are numerous non-immunological risk factors for chronic rejection which probably interact with immune components causing gradual graft failure. Xenotransplantation, where tissue is transferred across species, causes rejection by processes analogous to those seen in allografts but they are faster and more vigorous. Novel approaches have overcome some early antibody mediated rejection events but then reveal a huge, intense, adaptive cellular response. We believe that by the careful study of the mechanisms of rejection, the problems of chronic rejection and xenograft rejection will be overcome, thus reversing the widening gap between organ demand and supply.

What proportion of primary psychiatric interventions are based on evidence from randomised controlled trials?

OBJECTIVES: To estimate the proportion of psychiatric inpatients receiving primary interventions based on randomised controlled trials or systematic reviews of randomised controlled trials. DESIGN: Retrospective survey. SETTING: Acute adult general psychiatric ward. SUBJECTS: All patients admitted to the ward during a 28 day period. MAIN OUTCOME MEASURES: Primary interventions were classified according to whether or not they were supported by evidence from randomised controlled trials or systematic reviews. RESULTS: The primary interventions received by 26/40 (65%; 95% confidence interval (95% CI) 51% to 79%) of patients admitted during the period were based on randomised trials or systematic reviews. CONCLUSIONS: When patients were used as the denominator, most primary interventions given in acute general psychiatry were based on experimental evidence. The evidence was difficult to locate; there is an urgent need for systematic reviews of randomised controlled trials in this area.

Continuing medical education needs of rural GPs in South Australia.

The very extent of the information that was sought in the questionnaire may have contributed to the relatively small (33%) response rate. However, as stated, it is considered that the information received is sufficiently representative to help planners and providers of CME to ensure that their programs are fulfilling the genuine needs of rural practitioners in South Australia. It is accepted that educational needs are not static; they are always changing due to changing circumstances, changing skill requirements and constantly changing due to changing medical knowledge. The information gained from this survey will require regular updating, and this will be undertaken.

Hospital and general practice co-operative initiatives in education.

All these developments demonstrate what can be achieved by the presence, within the teaching hospital system, of a person who is recognised as being responsible for general practice training. Considerable progress has been made, but it is emphasised that this has been an evolutionary process. Further, almost all the programmes and activities that have evolved have been built on ideas initiated by the Director of Ambulatory Paediatrics or were already in the minds of a number of people but not implemented because of other commitments. The co-ordinator has been in a position to adopt these ideas and put them into practice.