Vascularized composite allografts contain various tissue components and possess relative antigenicity, eliciting different degrees of alloimmune responses. To investigate the strategies for achieving facial allograft tolerance, we established a mouse hemiface transplant model, including the skin, muscle, mandible, mucosa, and vessels. However, the immunomodulatory effects of the mandible on facial allografts remain unclear. To understand the effects of the mandible on facial allograft survival, we compared the diversities of different facial allograft-elicited alloimmunity between a facial osteomyocutaneous allograft (OMC), including skin, muscle, oral mucosa, and vessels, and especially the mandible, and a myocutaneous allograft (MC) including the skin, muscle, oral mucosa, and vessels, but not the mandible. The different facial allografts of a BALB/c donor were transplanted into a heterotopic neck defect on fully major histocompatibility complex-mismatched C57BL/6 mice. The allogeneic OMC (Allo-OMC) group exhibited significant prolongation of facial allograft survival compared to the allogeneic MC group, both in the presence and absence of FK506 immunosuppressive drugs. With the use of FK506 monotherapy (2 mg/kg) for 21 days, the allo-OMC group, including the mandible, showed prolongation of facial allograft survival of up to 65 days, whereas the myocutaneous allograft, without the mandible, only survived for 34 days. The Allo-OMC group also displayed decreased lymphocyte infiltration into the facial allograft. Both groups showed similar percentages of B cells, T cells, natural killer cells, macrophages, and dendritic cells in the blood, spleen, and lymph nodes. However, a decrease in pro-inflammatory T helper 1 cells and an increase in anti-inflammatory regulatory T cells were observed in the blood and lymph nodes of the Allo-OMC group. Significantly increased percentages of donor immune cells were also observed in three lymphoid organs of the Allo-OMC group, suggesting mixed chimerism induction. These results indicated that the mandible has the potential to induce anti-inflammatory effects and mixed chimerism for prolonging facial allograft survival. The immunomodulatory understanding of the mandible could contribute to reducing the use of immunosuppressive regimens in clinical face allotransplantation including the mandible.
Vascularized composite allotransplantation is an emerging strategy for the reconstruction of unique defects such as amputated limbs that cannot be repaired with autologous tissues. In order to ensure the function of transplanted limbs, the functional recovery of the anastomosed peripheral nerves must be confirmed. The immunosuppressive drug, tacrolimus, has been reported to promote nerve recovery in animal models. However, its repeated dosing comes with risks of systemic malignancies and opportunistic infections. Therefore, drug delivery approaches for locally sustained release can be designed to overcome this issue and reduce systemic complications. We developed a mixed thermosensitive hydrogel (poloxamer (PLX)-poly(l-alanine-lysine with Pluronic F-127) for the time-dependent sustained release of tacrolimus in our previous study. In this study, we demonstrated that the hydrogel drug degraded in a sustained manner and locally released tacrolimus in mice over one month without affecting the systemic immunity. The hydrogel drug significantly improved the functional recovery of injured sciatic nerves as assessed using five-toe spread and video gait analysis. Neuroregeneration was validated in hydrogel–drug-treated mice using axonal analysis. The hydrogel drug did not cause adverse effects in the mouse model during long-term follow-up. The local injection of encapsulated-tacrolimus mixed thermosensitive hydrogel accelerated peripheral nerve recovery without systemic adverse effects.
Rosacea is a chronic dermatosis with no cure. Our goal was to evaluate if the combination of flashlamp-pumped Pulsed Dye Laser (PDL) treatment with topical imiquimod could improve therapeutic outcomes. Fourty patients diagnosed with rosacea and aged between 16 and 53 years were assigned for three different types of treatment: i) PDL-only, ii) imiquimod-only, and iii) PDL + imiquimod. The PDL test sites received a single treatment with the VBeam laser (λ = 595 nm; spot size = 7 mm; tp = 1500 msec) at a dosage of 10 J/cm2 with cryogen spurt duration (30 msec) and the delay time (20 msec). For the test sites of PDL + imiquimod and imiquimod-only, the patients applied imiquimod topically to the test sites once a day for 1 month. Patients were followed-up at 1, 3, and 6 months. The primary efficacy was measured with a DermoSpectrometer. Patients were also monitored for adverse effects. Pair-wise analysis showed statistically significant differences between the blanching responses for the PDL + imiquimod and PDL-only and imiquimod-only treatments (p<0.005). Transient hyperpigmentation was noted in 5% (n=2) and 20% (n=8) of patients in the PDL + imiquimod and PDL-only treatment, respectively. Hyperpigmentation resolved spontaneously within 6 months. Permanent hypopigmentation or scarring was not observed. Superior blanching responses were obtained when using PDL + imiquimod than PDL-only or imiquimod-only treatment for rosacea. A larger number of patients are required to support the results of this study.
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