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Korean Journal of Transplantation Dec 2023
PubMed: 37994081
DOI: 10.4285/kjt.23.0050 -
Journal For Immunotherapy of Cancer Sep 2023Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the...
BACKGROUND
Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus.
METHODS
In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in "regressor" models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure.
RESULTS
Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood.
CONCLUSIONS
Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients.
Topics: Humans; Animals; Mice; Tacrolimus; Tacrolimus Binding Protein 1A; Immunosuppressive Agents; Skin Neoplasms; Immunocompromised Host
PubMed: 37678918
DOI: 10.1136/jitc-2023-006783 -
Biomaterials Translational 2023Infection and rejection in musculoskeletal trauma often pose challenges for natural healing, prompting the exploration of biomimetic organ and tissue transplantation as... (Review)
Review
Infection and rejection in musculoskeletal trauma often pose challenges for natural healing, prompting the exploration of biomimetic organ and tissue transplantation as a common alternative solution. Polyhydroxyalkanoates (PHAs) are a large family of biopolyesters synthesised in microorganism, demonstrating excellent biocompatibility and controllable biodegradability for tissue remodelling and drug delivery. With different monomer-combination and polymer-types, multi-mechanical properties of PHAs making them have great application prospects in medical devices with stretching, compression, twist in long time, especially in musculoskeletal tissue engineering. This review systematically summarises the applications of PHAs in multiple tissues repair and drug release, encompassing areas such as bone, cartilage, joint, skin, tendons, ligament, cardiovascular tissue, and nervous tissue. It also discusses challenges encountered in their application, including high production costs, potential cytotoxicity, and uncontrollable particle size distribution. In conclusion, PHAs offer a compelling avenue for musculoskeletal system applications, striking a balance between biocompatibility and mechanical performance. However, addressing challenges in their production and application requires further research to unleash their full potential in tackling the complexities of musculoskeletal regeneration.
PubMed: 38282701
DOI: 10.12336/biomatertransl.2023.04.004 -
Experimental & Molecular Medicine Aug 2023Keloid disorder is an abnormal fibroproliferative reaction that can occur on any area of skin, and it can impair the quality of life of affected individuals. To...
Keloid disorder is an abnormal fibroproliferative reaction that can occur on any area of skin, and it can impair the quality of life of affected individuals. To investigate the pathogenesis and develop a treatment strategy, a preclinical animal model of keloid disorder is needed. However, keloid disorder is unique to humans, and the development of an animal model of keloid disorder is highly problematic. We developed the patient-derived keloid xenograft (PDKX), which is a humanized mouse model, and compared it to the traditional mouse xenograft model (transplantation of only keloid lesions). To establish the PDKX model, peripheral mononuclear cells (PBMCs) from ten keloid patients or five healthy control subjects were injected into NOD/SCID/IL-2Rγnull mice, and their keloid lesions were grafted onto the back after the engraftment of immune cells (transplantation of keloid lesions and KP PBMCs or HC PBMCs). Four weeks after surgery, the grafted keloid lesion was subjected to histologic evaluation. Compared to the traditional model, neotissue formed along the margin of the grafted skin, and lymphocyte infiltration and collagen synthesis were significantly elevated in the PDKX model. The neotissue sites resembled the margin areas of keloids in several respects. In detail, the levels of human Th17 cells, IL-17, HIF-1a, and chemokines were significantly elevated in the neotissue of the PDKX model. Furthermore, the weight of the keloid lesion was increased significantly in the PDKX model, which was due to the proinflammatory microenvironment of the keloid lesion. We confirmed that our patient-derived keloid xenograft (PDKX) model mimicked keloid disorder by recapitulating the in vivo microenvironment. This model will contribute to the investigation of cellular mechanisms and therapeutic treatments for keloid disorders.
Topics: Humans; Mice; Animals; Keloid; Heterografts; Quality of Life; Mice, Inbred NOD; Mice, SCID; Fibroblasts; Disease Models, Animal
PubMed: 37524866
DOI: 10.1038/s12276-023-01045-6 -
The Journal of Investigative Dermatology Oct 2023Pluripotent stem cells have the potential to become any cell type, and recently, they have been used to create organoids that can recapitulate several pertinent features...
Pluripotent stem cells have the potential to become any cell type, and recently, they have been used to create organoids that can recapitulate several pertinent features of human organs. Skin organoids have been developed that possess many of the crucial accessory organs, including hair follicles, sebaceous glands, nerves, fat, and melanocytes. These skin organoids present the opportunity to study skin development and disease as well as perform screens to identify new drug candidates. In the future, skin organoids might augment clinical practice by serving as source material for transplantation to treat wounds or other conditions. Nevertheless, several limitations, such as the lengthy differentiation protocol, which can result in heterogeneous products, must first be addressed before the full potential of skin organoids can be realized. The purpose of this article is to provide a broad overview of skin organoids so that a broader audience can become familiar with this technology, which has important implications for dermatologic research and medicine.
Topics: Humans; Dermatology; Skin; Organoids; Sebaceous Glands; Pluripotent Stem Cells
PubMed: 37739763
DOI: 10.1016/j.jid.2023.07.017 -
The Journal of Clinical Endocrinology... Sep 2023Imbalance of the skin microbial community could impair skin immune homeostasis and thus trigger skin lesions. Dysbiosis of skin microbiome may be involved in the early...
CONTEXT
Imbalance of the skin microbial community could impair skin immune homeostasis and thus trigger skin lesions. Dysbiosis of skin microbiome may be involved in the early pathogenesis of diabetic foot (DF). However, the potential mechanism remains unclear.
OBJECTIVE
To investigate the dynamic composition and function of the foot skin microbiome with risk stratification for DF and assess whether dysbiosis of the skin microbiome induces diabetic skin lesions.
METHODS
We enrolled 90 consecutive subjects who were divided into 5 groups based on DF risk stratification: very low, low, moderate, and high risk for ulcers and a healthy control group. Integrated analysis of 16S ribosomal RNA and metagenomic sequencing of cotton swab samples was applied to identify the foot skin microbiome composition and functions in subjects. Then a mouse model of microbiota transplantation was used to evaluate the effects of the skin microbiome on diabetic skin lesions.
RESULTS
The results demonstrated that, with the progression of diabetic complications, the proportion of gram-negative bacteria in plantar skin increased. At the species level, metagenome sequencing analyses showed Moraxella osloensis to be a representative core strain in the high-risk group. The major microbial metabolites affecting diabetic skin lesions were increased amino acid metabolites, and antibiotic resistance genes in microorganisms were abundant. Skin microbiota from high-risk patients induced more inflammatory cell infiltration, similar to the lipopolysaccharide (LPS)-stimulated response, which was inhibited by Toll-like receptor 4 (TLR4) antagonists.
CONCLUSIONS
The skin microbiome in patients with diabetes undergoes dynamic changes at taxonomic and functional levels with the progression of diabetic complications. The increase in gram-negative bacteria on the skin surface through LPS-TLR4 signal transduction could induce inflammatory response in early diabetic skin lesions.
Topics: Mice; Animals; Humans; Diabetic Foot; Lipopolysaccharides; Toll-Like Receptor 4; Dysbiosis; Gram-Negative Bacteria; Risk Factors; RNA, Ribosomal, 16S; Diabetes Mellitus
PubMed: 36974462
DOI: 10.1210/clinem/dgad178 -
Cureus Oct 2023Severe combined immunodeficiency (SCID) is a rare condition with very high mortality. SCID is mainly caused by the multiple mutations of genes affecting the entire... (Review)
Review
Severe combined immunodeficiency (SCID) is a rare condition with very high mortality. SCID is mainly caused by the multiple mutations of genes affecting the entire immune cells. Children with this disease are born with an impaired immune system. The child appears healthy but the consequences of the impaired immune system lead to various secondary infections such as meningeal infections and respiratory infections further leading to consolidation, diarrhea, inflammation of skin and other systemic diseases. Severe combined immunodeficiency is also known as "bubble boy disease" or "living in the bubble" syndrome, as in early days for treatment the physicians decided to completely isolate them until they got the perfect match for the bone marrow transplantation. It is one of the pediatric emergencies and is to be treated as soon as possible. SCID involves multiple genes which leads to makes diagnosis of the disease cumbersome. In early years many infants were diagnosed almost after half a year and in severe conditions which led to the decrease in the survival rate of the children. But now due to advanced newborn screening modalities and other monitoring systems it can be diagnosed as early as within three months of age. The various treatment modalities include hematopoietic stem cell transplantation, gene therapy, enzyme replacement therapy and chemotherapy. This narrative review article describes about the severe combined immunodeficiency and its newer treatment modalities.
PubMed: 38022338
DOI: 10.7759/cureus.47759 -
The Journal of Allergy and Clinical... Dec 2023Exposure to insects used in pet food, scientific research, or live fish bait can cause an occupational allergy. The recent shift toward enhanced insect production for...
BACKGROUND
Exposure to insects used in pet food, scientific research, or live fish bait can cause an occupational allergy. The recent shift toward enhanced insect production for human consumption and animal feed will likely expose more employees.
OBJECTIVE
To investigate sensitization and symptoms in employees exposed to edible insects in Flanders.
METHODS
Fifteen insect-exposed employees were recruited and sensitization was explored by skin prick test, basophil activation test, and immunoblotting. Lung function, FeNO, histamine provocation, and sputum induction were studied. Airborne dust sampling was performed and proteins were studied by silver stain and immunoblotting.
RESULTS
Sixty percent of employees self-reported upper respiratory tract symptoms related to insect exposure. Ten employees (71.4%) had a positive histamine provocation test concentration causing a 20% drop in FEV1 less than 8 mg/mL and four (26.7%) had FeNO levels above 25 ppb. Four employees (30.7%) had a positive skin prick test for at least one insect, and seven (58.3%) had a positive basophil activation test. In eight participants with insect sensitization, four (50%) had co-occurring house dust mite sensitization. Two participants had strong IgE binding to a 50-kDa migratory locust allergen, one to a 25-kDa mealworm allergen, and one to mealworm α-amylase. In one center, facility adjustment resulted in a substantial decrease in the inhalable dust fraction.
CONCLUSIONS
Insect exposure leads to high levels of sensitization among employees. Most employees reported symptoms of the upper respiratory system, and two-thirds of employees had bronchial hyperreactivity. Prevention and health surveillance will be important in the developing insect-rearing industry.
Topics: Animals; Humans; Edible Insects; Histamine; Hypersensitivity; Allergens; Dust; Skin Tests
PubMed: 37543086
DOI: 10.1016/j.jaip.2023.07.039 -
International Journal of Molecular... Aug 2023Most of the knowledge about human skin homeostasis, development, wound healing, and diseases has been accumulated from human skin biopsy analysis by transferring from... (Review)
Review
Most of the knowledge about human skin homeostasis, development, wound healing, and diseases has been accumulated from human skin biopsy analysis by transferring from animal models and using different culture systems. Human-to-mouse xenografting is one of the fundamental approaches that allows the skin to be studied in vivo and evaluate the ongoing physiological processes in real time. Humanized animals permit the actual techniques for tracing cell fate, clonal analysis, genetic modifications, and drug discovery that could never be employed in humans. This review recapitulates the novel facts about mouse skin self-renewing, regeneration, and pathology, raises issues regarding the gaps in our understanding of the same options in human skin, and postulates the challenges for human skin xenografting.
Topics: Humans; Animals; Mice; Transplantation, Heterologous; Skin; Heterografts; Wound Healing; Biopsy
PubMed: 37628950
DOI: 10.3390/ijms241612769 -
Zhongguo Xiu Fu Chong Jian Wai Ke Za... Jul 2023To summarize the research progress of surgical technique and immunosuppressive regimen of abdominal wall vascularized composite allograft transplantation in animals and... (Review)
Review
OBJECTIVE
To summarize the research progress of surgical technique and immunosuppressive regimen of abdominal wall vascularized composite allograft transplantation in animals and clinical practice.
METHODS
The literature on abdominal wall transplantation at home and abroad in recent years was extensively reviewed and analyzed.
RESULTS
This review includes animal and clinical studies. In animal studies, partial or total full-thickness abdominal wall transplantation models have been successfully established by researchers. Also, the use of thoracolumbar nerves has been described as an important method for functional reconstruction and prevention of long-term muscle atrophy in allogeneic abdominal wall transplantation. In clinical studies, researchers have utilized four revascularization techniques to perform abdominal wall transplantation, which has a high survival rate and a low incidence of complications.
CONCLUSION
Abdominal wall allotransplantation is a critical reconstructive option for the difficulty closure of complex abdominal wall defects. Realizing the recanalization of the nerve in transplanted abdominal wall to the recipient is very important for the functional recovery of the allograft. The developments of similar research are beneficial for the progress of abdominal wall allotransplantation.
Topics: Animals; Abdominal Wall; Vascularized Composite Allotransplantation; Transplantation, Homologous; Skin Transplantation; Hematopoietic Stem Cell Transplantation
PubMed: 37460189
DOI: 10.7507/1002-1892.202302077