Assessment of the PKM2 enzyme as a target for immune modulation during rejection responses in vascularized composite allografts

• Grant number: 21/13641-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: May 15, 2022
• End date: May 08, 2023
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Daniel Marconi Mendes
• Supervisor: Leonardo Vidal Riella
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Massachusetts General Hospital, United States
• Associated to the scholarship: 20/04430-3 - Role of the PKM2 enzyme in the regulation of the immune and metabolic responses of keratinocytes in an experimental model of skin transplantation, BP.DD

Abstract

The first studies with solid organ transplantation (SOT) date from the beginning of the 20th century. But, due to the scarcity of surgical and immunological knowledge at the time, the results were unsatisfactory due to the graft rejection and death of the recipients. It was only with the discovery of the MHC molecule, improvement in surgical techniques and graft preservation, as well as the discovery of immunosuppressive drugs that such procedures began to be widely used in the clinic. However, although the use of such immunosuppressive drugs prevents graft rejection, such drugs may lead to several negative consequences for the organ recipient including nephrotoxicity, susceptibility to opportunistic infections, diabetes and the development of neoplasms. Until now, one of the biggest challenges in allograft transplantation is the modulation and control of the host immune responses against the transplanted graft and the side effects that arise from it. Recently, composite vascularized allografts (VCA) have emerged as a new frontier in the transplant immunology field. VCAs can be broadly defined as vascularized grafts composed of multiple tissues such as bones, nerves, muscles, blood vessels and skin, this type of graft represents a major advance in reconstructive surgery for individuals with severe damage to non-vital body parts, thus allowing for the restoration of form and function of the damaged body portion. However, VCA recipients are associated with over 90% post-transplantation rejection rate and require a higher level of immunosuppression due to the immunogenic nature of the skin grafts and this long-term immunosuppression predisposes VCA transplant patients to the risks associated with such an immunosuppressive regimen, therefore, alternative methods to regulate the immune system are needed to minimize drug toxicity. Recently, several studies have shown that cell metabolism plays a key role in the activation and regulation of immune responses in the body, highlighting the importance of studies that elucidate the role of cell metabolism in the context of transplant immunology. In general, immune cells activated by antigens or cytokines become highly migratory and proliferative, which demands a high energy expenditure, triggering a phenomenon called the Warburg effect; where cells start using the glycolytic pathway as their main source of energy even in the presence of oxygen (glycolysis aerobics) thus allowing a rapid generation of energy and the accumulation of metabolic precursors that will be essential for the effector functions of these immune cells. Literature data have already shown that the pyruvate kinase M2 (PKM2) enzyme plays a key role in the development of the Warburg effect, this enzyme acts in the last step of glycolysis and also in the transcription of genes associated with the Warburg effect, thus ensuring energy levels and molecular precursors for the production of macromolecules, cell proliferation and migration, all fundamental processes for the immune response development. Thus, considering that immune cells, when activated by pro-inflammatory signals, need a metabolic shift through the Warburg effect, which then guarantees the supply of energy and biomolecules to proliferate, migrate and produce different pro-inflammatory molecules that contribute to graft rejection and since the PKM2 enzyme is a pivotal component in the development of the Warburg effect, possibly PKM2 is involved in the modulation of immune responses during VCA transplant rejection. Therefore, investigating the role of this enzyme as a possible therapeutic target that serves as an alternative to current immunosuppression strategies used in the clinical practice of VCA transplants are of paramount importance to improve the outcomes of these surgical procedures by preventing graft rejection events and reducing the side effects of immunosuppressive regimens. (AU)