Manipulating Stress Receptor Signaling to Enhance Immunosuppression and Prolong Survival of Vascularized Composite Tissue

Vascularized composite tissue allotransplantation (VCA) can replace severely damaged body parts but the unavoidable toxicity of high doses of immunosuppressive drugs, such as tacrolimus, required results in significant morbidity. Here we tested whether we could suppress immune activity in a mouse model of VCA by mimicking the natural immune suppression generated by nervous system-induced signaling of adrenergic receptors (AR) by using a safe and well-studied β-AR agonist (terbutaline). Using wild-type and β2-AR-knockout (KO) mice, we found that increased β2-AR signaling results in delayed rejection in VCA recipients, even with subtherapeutic doses of tacrolimus, and this was associated with changes in immune contexture, expression of pro-inflammatory cytokines and chemokines, and function of endothelial adhesion molecules. We propose that β-AR agonists can be used safely to mimic the natural suppression of immune responses generated by adrenergic stress signaling and thereby reduce the dose needed of other more toxic immunosuppressive drugs.

Hand Transplantation—Risks and Benefits

Composite tissue allotransplantation (CTA) is the culmination of progress in transplantation, allowing the reconstruction of the hand in amputees. Worldwide, more than 100 procedures have been performed. The aim of this work was to understand the hand allotransplantation approach, making known current aspects, risks, and benefits. A PubMed research was realized between October 2018 and March 2019, including terms like “Hand transplantation” AND “Composite tissue allotransplantation,” “Hand transplantation” AND “Functional outcomes,” “Hand transplantation” AND “Immunosuppression,” “Hand prosthetics,” “Hand Transplantation” AND “Ethics.” There were included papers between 1995 and 2018, with English language, amputee human adults, systematic reviews, and clinical studies. Seventy-two papers were fully evaluated. There are technical aspects that influence the procedure like team coordination or surgical technique. It requires a long-life treatment, which has risks such as toxicity or infections. However, it allows the recovery of fine movements, and independence, to perform detailed tasks. The indications must be carefully considered, because some patients benefit from the use of prosthesis. CTA has become an option for amputees so it is important to do more research, to determine the benefits of this procedure. It is not considered a life-saving procedure, so there is an ethical debate because of the risks.

Vascularized Composite Allotransplantation in Burn Reconstruction: Systematic Review and Meta-analysis

Vascularized composite allotransplantation has been successfully employed for burn reconstruction since 2003. However, its safety in this population has been questioned due to high levels of alloimmunization from burn care-related tissue exposures. To investigate this, a systematic review of vascularized composite allotransplantation employed for burn reconstruction was conducted, evaluating literature from January 2000 to September 2019. Articles containing vascularized composite allotransplantation, composite tissue allotransplantation, and burn reconstructive surgery were included; articles without published outcomes were excluded. Observational meta-analysis of pooled mortality and acute rejection episodes relative to allograft type (face vs extremity) and reconstruction type (burn vs non-burn) was performed. Twenty-four of the 63 identified articles met the criteria for inclusion, with 5 more articles added after secondary review. To date, 152 allotransplantations have been performed in 117 patients: 45 face transplants and 107 extremity transplants. Of these, 34 (22%) were performed for burn reconstruction in 25 patients (21%) with an overall higher 1-year mortality rate (12.0% vs 1.1%, P = .030). Of these deaths, 75% received three or more simultaneous allografts. Additionally, more episodes of acute rejection occurred compared to non-burn patients (4.4 vs 2.4, P = .035). Vascularized composite allotransplantation performed for burn reconstruction was found to be associated with a greater risk of 1-year mortality and nearly twice the number of episodes of acute rejection. Future studies should seek to identify unique risk factors of burn patients undergoing this operation and evaluate the relationship between antigenic burden and surgical outcomes.

Predicting Outcomes of Rat Vascularized Composite Allotransplants through Quantitative Measurement of Chimerism with PCR-Amplified Short Tandem Repeat

Chimerism has been associated with the induction and maintenance of tolerance to vascularized composite allotransplants (VCA). Although most VCA studies have examined chimerism using flow cytometry, we proposed that precision in the measurement of chimerism may be better approximated when complimentary polymerase chain reaction (PCR) is applied to a specific short tandem repeat (STR). We identified a STR, D10Rat25, which exhibited a ~20 bp difference in length between two rat strains (BN and LEW) often utilized as the donor and recipient in many allotransplantation studies. D10Rat25 was PCR-amplified and quantified with capillary electrophoresis. With pure LEW and BN DNA, a standard curve was constructed to measure chimerism with good linearity. When applied to rat VCA, the relationship between systematic (in peripheral blood) or local (at specific organ/tissues) chimerism to allograft outcomes was noted. We found that peripheral chimerism was elevated by up to ~9% postoperative month 1 (POM 1) but then reduced regardless of the final VCA outcome. However, differences in VCA skin chimerism between early rejection and POM 1 (shown as ΔChimerismPOM1-ER) were notable with respect to VCA outcomes. ROC analysis identified the optimum cutoff value as 17.7%. In summary, we have developed a reliable method to quantify the percentage of BN cells/DNA in BN-LEW chimeras. The detection limit was characterized, and the acquired data were comparable with flow cytometry. This method can be applied to solid organ and composite tissue allotransplantation studies.

Face transplantation

Facial composite tissue allotransplantation is an emerging field which offers the potentially restore facial form and function, even following the most severe traumatic injuries. This benefit must be carefully weighed against the need to lifelong immunosuppression, associated infection risks, and possible rejection. Patients must be carefully screened for medical and psychiatric issues prior to the procedure. However, in the well-selected patient, this procedure can be transformative. Uniformly, patients self-report a dramatic improvement post transplantation. In addition, return of sensation in the transplanted allograft occurs in 3–6 months, although return of motor function takes longer and remains incomplete. Ultimately, facial composite tissue transplantation is a powerful technique in the properly selected patient.