Journal of immunology and regenerative medicine最新文献

Progress in human pluripotent stem cells has opened up an opportunity to autologous β-cell replacement therapies in patients with diabetes. Such an approach could render immunologically compatible islets from an unconstrained source without requirement for chronic immune suppression. Several proof-of-concept studies have generated stem cell-derived islets (SC-islets) capable of reversing diabetes in rodents and with similar functional characteristics to human donor islets. Autologous SC-islets offer potential to improve the life of patients living with diabetes by enabling cell replacement therapy that provides physiologic glycemic control with less risk to the recipient. Such efforts are impeded from ongoing challenges in scalability, latent potential for teratogenicity, an inability to fully recapitulate metabolic responses observed with primary islets, and protection from autoimmune recurrence in the setting of Type 1 diabetes. In this review, we outline potential opportunities and impediments for successful clinical translation of SC-islets as an effective therapy for patients with all forms of diabetes. We discuss recent advancements in scale-up manufacturing, the promise of gene-editing for optimized cellular protection, and methods to deliver safe and immune shielded cells to improve engraftment and survival. Finally, we discuss in detail goals and challenges in islet bioengineering and emphasize the need for improved methods to overcome the roadblocks in translating autologous SC-islet cell therapies to the clinic.

Macrophages can be found in various tissues and play an important role in organ function by sensing and eradicating pathogens, regulating immune responses and contributing to tissue homeostasis and repair. Nowadays, increasing numbers of macrophage-based cell therapies are entering (pre-) clinical studies e.g. for the treatment of liver cirrhosis. Given limited availability of suitable donors as well as problems with variability in quantities and qualities of human monocytes that can be derived from apheresis, induced pluripotent stem cells (iPSC) offer an attractive source of therapeutic macrophages. However, considering the diverse functions, activation stages and overall plasticity of macrophages, further knowledge about (i) the potential to induce different activation stages in iPSC-derived macrophages (iPSC-Mac) as well as (ii) the stability of these phenotypes upon additional external stimuli is of high relevance. We here demonstrate that iPSC-Mac produced in a scalable differentiation platform can be polarized into defined pro- (M1) and anti-inflammatory (M2) activation stages characterized by specific surface marker expression, cytokine secretion and whole transcriptome analysis, similarly to peripheral blood-derived macrophages. Even more importantly, we show that differentially polarized iPSC-Mac maintained key characteristics of their activation status upon a subsequent inflammatory trigger. Interferon (IFN) γ polarized, M1-iPSC-Mac demonstrated an enhanced inflammatory response after additional lipopolysaccharide (LPS) stimulation, whereas Interleukin (IL)-4 stimulated M2a iPSC-Mac and IL-10/TGFβ primed M2c iPSC-Mac showed a reduced activation upon LPS treatment and maintained expression of anti-inflammatory genes. Together, our data demonstrate that defined polarized iPSC-Mac subsets can be generated. Moreover, these cells maintain key characteristics of their activation profile upon a subsequent inflammatory trigger. Thus, the use of stably polarized iPSC-Mac has the potential to further improve the applicability and efficacy of macrophage-based therapies.

Islet transplantation is a promising therapy for a subset of people with Type 1 diabetes (T1D). However, beta cell transplant clinical trials have largely failed to maintain long-term normal glycemia in transplant recipients. This is broadly due to immune rejection of the transplanted islets themselves or the devices in which these cells are encapsulated. As an autoimmune condition, the T1D host presents a uniquely challenging immunological niche for the transplant of additional beta cells. An understanding of the autoimmune environment is crucial for the development of successful beta cell transplant therapies. Here, we provide an overview of the immune cell pathways leading to autoimmune T1D, and the resulting immune niche. Next, we examine biomaterial platforms that can be used for cell transplantation, and describe those that seek to modulate the immune environment to mitigate immune rejection. These approaches include delivery of localized immune cues, co-transplantation with immunomodulatory cells, strategies to engineer islets ex-vivo, and antigen-specific immunomodulation to generate operational tolerance. Finally, we describe therapies which seek to prevent T1D progression which could be repurposed to support beta cell transplantation and future immunoengineering design considerations for successful islet transplantation therapies.

Cytokine manipulation has been widely used to bolster innate healing mechanisms in an array of modern therapeutics. While other anatomical locations have a more definitive analysis of cytokine data, the tendon presents unique challenges to detection that make a complete portrayal of cytokine involvement during injury unattainable thus far. Without this knowledge, the advancement of tendon healing modalities is limited. In this review, we discuss what is known of the cytokine profile within the injured tendinous environment and the unique obstacles facing cytokine detection in the tendon while proposing possible solutions to these challenges. IL-1β, TNF-α, and IL-6 in particular have been identified as key cytokines for initiating tendon healing, but their function and temporal expression are still not well understood. Methods used for cytokine evaluation in the tendon including cell culture, tissue biopsy, and microdialysis have their strengths and limitations, but new methods and approaches are needed to further this research. We conclude that future study design for cytokine detection in the injured tendon should meet set criteria to achieve definitive characterization of cytokine expression to guide future therapeutics.

Objectives

For nearly a century, the therapeutic use of exogenous insulin remains the gold standard treatment strategy for patients living with Type 1 Diabetes Mellitus (T1DM). While lifesaving, insulin can fail to prevent the secondary vascular disease and complications inherited with T1DM diagnosis, and for some, this may increase their risk of life-threatening hypoglycemic unawareness. In recent decades transplantation has been demonstrated as the only means (a replacement gold standard therapy) to effectively restore physiologically relevant glycemic control. Moreover, significant advancements in clinical islet transplantation have yielded greater incidences of durable insulin-independence, rescindment of critical hypoglycemia and prevention of comorbidities. Yet, the requisite of life-long immunosuppression and scarcity of a universal and potent cell supply, in addition to the challenges faced with such therapy in vivo, restricts the broad-spectrum application of cell-based therapies.

Key findings

Herein, this review presents the history, current status and persisting challenges confronting cell-based replacement therapies for T1DM. Lastly, we examine modern and future research opportunities designed to enhance the efficacy of cellular transplantation, thereby offering a potential functional cure to all those affected by T1DM.

Conclusions

Given the rapid progress in β-cell replacement therapy, it is hopeful that through multidisciplinary innovations, first-in-human stem cell trials, innocuous immunosuppression and efficacious extrahepatic transplant sites, β-cell replacement therapies will become the cornerstone treatment for the millions worldwide afflicated with T1DM.