Research Program
The interdisciplinary nature of exTra is critical to achieving its goal of better understanding the immunological effects of ECP in transplant recipients. The design and quality of the partners’ scientific and clinical research will be greatly enhanced through consortium interactions – our immunological studies will be more focused on key clinical questions and mechanistic studies will add value to our clinical trials.
The tightly-focused exTra research programme has been structured into four research work-packages (WP) to reflect its principal areas of innovation (Figure 3). The exTra project combines 11 diverse, but interrelating research projects ranging from basic molecular and cellular biology through preclinical and manufacturing development to clinical applications. Additionally, WP5-8 will support network-wide training activities, data management, scientific standards, project management, DoC recruitment and consortium communications.
exTra comprises four research packages, namely (WP1) Immune regulation, (WP2) Antibody responses, (WP3) Tissue repair, and (WP4) Immune pharmacology.
WP1-3 reflect the 3 areas where ECP is most likely to impact care of solid organ transplant patients over the next 5 years. Innovation in these WPs will be accelerated by discoveries from WP4, which focuses on the immunopharmacology of ECP. We anticipate exploitable results from all 4 WP, including novel applications of ECP and new in vitro diagnostic tests.
Work Package 1 – Immune regulation
WP1 is led by Dr. Niloufar Safinia of Kings College London, United Kingdom.
WP1 explores ECP as an alternative form of induction therapy to avoid high-dose immunosuppression early after transplantation. ECP is clearly effective in suppressing T cell-mediated pathologies, including acute GVHD, so we expect that ECP can also suppress T cell alloimmunity after solid organ transplantation, reducing the need for early high-dose immunosuppression. Consequently, we see important potential applications for ECP induction therapy in patients who might benefit from avoidance of conventional immunosuppression in the immediate post-operative period; for instance, in transplant recipients at high risk of transplant-related infections (Gökler, J. Transpl Int. 2022) or liver transplant recipients vulnerable to CNI-associated renal failure (Urbani, L. J. Clin. Apheresis. 2007; Schnitzbauer, A. Transplantation. 2015). Interestingly, it has been claimed that ECP restores immune homeostasis through diverse immunoregulatory cell subsets, including regulatory T cells (Tregs), regulatory B cells (Bregs), ‘modulated’ NK cells, myeloid-derived suppressor cells (MDSC) and tolerogenic dendritic cells (DC). Therefore, ECP induction therapy could also be useful in establishing allospecific immune regulation early after transplantation. WP1 tackles ECP induction therapy through subprojects at world-class clinical research labs focusing on Tregs (DoC1), NK cells and MDSC (DoC2) and Bregs (DoC3).
WP2 considers the impact of ECP on humoral immunity. It is known that ECP reduces donor-specific antibody (DSA) titres in heart, lung and kidney transplant recipients (Benazzo, A. Transfus Med Hemother. 2020). However, ECP seems not to impair protective antibody responses and it’s not an effective treatment for classical antibody-mediated autoimmune diseases, such as myasthenia gravis. The most likely explanation for this differential therapeutic effect is that ECP suppresses T cell-dependent antibody production by memory B cells, but can’t suppress antibody production by long-lived plasma cells.
Antibody-mediated allograft injury is a major contributor to acute and chronic transplant dysfunction and loss, which is poorly controlled with current immunosuppression. Through 3 subprojects in outstanding basic or clinical research groups, WP2 addresses potential applications of ECP in preventing antibody-mediated rejection (ABMR) in kidney transplant recipients and preventing chronic lung allograft dysfunction (CLAD) in lung transplant recipients with persistently elevated DSA.
Work Package 2 - Antibody responses
WP2 is led by Anja ten Brinke of Stichting Sanquin Bloedvoorziening, Amsterdam, the Netherlands.
Work Package 3 – Tissue repair
WP3 is led by Prof. Elke Eggenhofer of University Hospital Regensburg, Germany
WP3 explores the potential for ECP to resolve tissue damage by suppressing early innate inflammation or stimulating tissue-repair. Unlike applications of ECP in inflammatory disorders, using ECP to directly promote repair processes has not been previously investigated. WP3 builds upon basic scientific discoveries showing that monocytes exposed to apoptotic cells acquire tissue-reparative properties, as well as evidence from patients with acute liver injury or liver transplants, showing the importance of tissue-repair macrophages in resolution of extensive liver damage (Moroni, F. Nat Med. 2019). We see impactful clinical indications for ECP in preventing inflammation after ischemia-reperfusion injury (IRI) and as a potential “bridging therapy” for patients with acute liver failure who are wait-listed for time-critical liver transplantation
WP4 is a preclinical research package that aims to develop and validate in vitro diagnostic (IVD) assays for pharmaceutical testing of photopheresates, as well as pharmacological monitoring of responses to ECP in organ transplant recipients. WP4 will also explore the hypothesis that the living cell fraction and acellular components of photopheresates also exert clinically important effects.
Work Package 4 - Immune pharmacology
WP4 is led by Prof. Holger Hackstein by Univ. Hospital Erlangen, Germany