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Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA‐A2 CAR‐Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL‐10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA‐A2, and suppressed alloresponses potently. The addition of IL‐10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof‐of‐principle for this cell engineering approach for next‐generation Treg therapy in transplantation., Chimeric antigen receptor (CAR) constructs can be modified to incorporate elements for enhanced activity. Here, human Tregs were modified to express an anti‐HLA‐A2 CAR as well as IL‐10 and an imaging reporter. These cells maintained a stable Treg phenotype after lentiviral transduction, were specifically activated by cells expressing HLA‐A2, and had enhanced in vitro suppressive potency compared with CAR Tregs without constitutive IL‐10 expression.

The humanization of animals is a powerful tool for the exploration of human disease pathogenesis in biomedical research, as well as for the development of therapeutic interventions with enhanced translational potential. Humanized models enable us to overcome biologic differences that exist between humans and other species, while giving us a platform to study human processes in vivo. To become humanized, an immune-deficient recipient is engrafted with cells, tissues, or organoids. The mouse is the most well studied of these hosts, with a variety of immunodeficient strains available for various specific uses. More recently, efforts have turned to the humanization of other animal species such as the rat, which offers some technical and immunologic advantages over mice. These advances, together with ongoing developments in the incorporation of human transgenes and additional mutations in humanized mouse models, have expanded our opportunities to replicate aspects of human allotransplantation and to assist in the development of immunotherapies. In this review, the immune and tissue humanization of various species is presented with an emphasis on their potential for use as models for allotransplantation, graft versus host disease, and regenerative medicine.

The limitations of using race in biomedicine are important to recognize because race is often afforded more biological value than can be scientifically justified — and less social value than it commands.

One of the critical questions facing the field of transplantation is how to control effector T cell activation yet simultaneously preserve regulatory T cell (Treg) function. Thus, standard calcineurin inhibitor-based strategies can partially control effector T cells (Teffs), but breakthrough activation still occurs, and these agents are antagonistic to Treg function. Conversely, mTOR inhibition with sirolimus is more Treg-compatible, but is inadequate to fully control Teff activation. In contrast,, blockade of OX40L signaling has the capacity to partially control Teff activation despite maintaining Treg function. Here we have used the non-human primate (NHP) GVHD model to probe the efficacy of combinatorial immunomodulation with sirolimus and the OX40L-blocking antibody KY1005. Our results demonstrate significant biologic activity of KY1005 alone (prolonging median GVHD-free survival from 8 to 19.5 days), as well as striking, synergistic control of GVHD with KY1005 + sirolimus (median survival time >100 days, p< 0.01 compared to all other regimens), which was associated with potent control of both Th/Tc1 and Th/Tc17 activation. Combined administration also maintained Treg reconstitution (resulting in an enhanced Treg:Tcon ratio (40% over baseline) in the KY1005/Sirolimus cohort compared to a 2.9-fold decrease in the unprophylaxed GVHD cohort). This unique immunologic signature resulted in transplant recipients that were able to control GVHD for the length of analysis, and to down-regulate donor/recipient alloreactivity despite maintaining anti-third-party responses. These data indicate that combined OX40L blockade and sirolimus represents a promising strategy to induce immune balance after transplant, and is an important candidate regimen for clinical translation.

George Adigbli gained more surgical experience during a two month elective in Brazil than during his two year foundation training

Neck haematomas are rare but potentially life-threatening complications of thyroid surgery. Postoperative monitoring, early diagnosis and immediate management are critical, as this condition can rapidly lead to compression and obstruction of the upper airway. We present a case of a 69-year-old woman who suffered respiratory failure resulting from a post-thyroidectomy haematoma with airway obstruction and severe haemodynamic compromise, presenting a difficult anaesthetic challenge. Following development of a likely ‘cannot intubate, cannot ventilate’ situation despite haematoma evacuation, the patient underwent emergency cricothyroidotomy, before rapid sequence intubation and subsequent surgical haemostasis.