Transplantation and autoimmunity

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Immunohematology and Blood Transfusion.

Aim and focus

Lack of immunological tolerance and a critical role for HLA-antigens is central to both autoimmunity and transplant rejection. While in autoimmune disease tolerance to self-antigens is lost, alloreactivity towards non-self HLA-molecules can lead to detrimental immune responses after organ and stem cell transplantation. The aim of the program is to prevent and modulate these unwanted immune responses. For this purpose, the molecular mechanisms that lead to these unwanted immune reactions are defined with the goal to use this knowledge for the development of preventive and curative protocols.

Position in international context

The laboratory in Leiden belongs to one of the top histocompatibility laboratories in the world and is well known for its research on the role of HLA in both Transplantation Immunology and Autoimmunity. The laboratory is the reference laboratory of the international organ exchange organization Eurotransplant. Members of the group are/have been board members (including president) and members of the scientific advisory boards of International Societies in the field of Immunogenetics, Histocompatibility and Transplantation and are represented in the editorial boards of the majority of journals dedicated to this research subject. Members of the team play a pivotal role in international organisations (National Marrow Donor Program, Bone Marrow Donors Worldwide, International Society for Blood Transfusion, European Federation for Immunogenetics, American Society for Histocompatibility and Immunogenetics, European Society for Organ Transplantation, Eurotransplant, Matchis). Members of the team play leading roles in research Consortia like the Celiac Disease Consortium and the Diabetes Centre.

Content / highlights / achievements

Next to optimal HLA matching in organ and hematopoietic stem cell transplantation, the research on the differential immunogenicity of HLA mismatches has been beneficial for our knowledge of the alloimmune response and has led to an increased success of HLA mismatched transplants. Studies on the immunomodulatory effect of exposure to non-inherited maternal HLA antigens has led to the identification of less immunogenic HLA mismatches. Recent research is aiming to understand the immunological mechanism by which a pregnant woman does not reject her HLA-mismatched foetus. This information can be used to develop protocols to induce transplantation tolerance.
Research into HLA-disease associations has led to the unravelling of the relationship between HLA-DQ2/8, gluten and development of celiac disease, in particular we identified the nature of the disease inducing gluten peptides and the role of enzymatic modification of gluten in the gastrointestinal tract as an important step towards disease development. In close collaboration with the group of Prof. J. Rossjohn (Melbourne, Australia), the molecular basis for the recognition of immunodominant gluten peptides by gluten-specific T cell receptors has been elucidated and this revealed a highly conserved mode of recognition by T cells from patients. Moreover, evidence for the involvement of cytokines produced by gluten-reactive T cells in the development of refractory celiac disease has been obtained, results that partly explain the preferential occurrence of this mostly fatal complication by patients that are homozygous for HLA-DQ2. In addition, mass cytometry has been successfully implemented and used to determine immune signatures in tissue that correlate with intestinal diseases. In close collaboration with partners within the LUMC and the TU Delft computational tools have been developed to aid in the analysis of the complex, high-dimensional datasets generated by mass cytometry. Most recently, imaging mass cytometry has been implemented and is expected to become fully operational early in 2018.
Also, we have identified the first naturally processed peptide beta-cell epitopes recognized by autoreactive T-cells in type I diabetes patients. These epitopes have been used to show that T1D is a Th1-dominated disease and to identify a novel subset of IL-10 producing autoreactive T cells, that is particularly prevalent in T1D patients with late age of onset, implying a role in retarding disease progression. Most recently a novel T cell epitope has been identified that is derived from a defective ribosomal insulin gene product. A protocol to re-establish tolerance to such peptide antigens with the use of tolerogenic dendritic cells has been developed and is currently tested in a phase 1 clinical trial.

Future themes

Induction of clinical transplantation tolerance based on the GMP production of immunomodulating cells (DCs, MSC). Application of immunomodulating DCs to re-introduce tolerance in TID. Further unravelling the role of the alloimmune response, including the degree of chimerism, in normal and deviated pregnancy and the differential immunogenicity of HLA mismatches in clinical transplantation. Implementation of enzyme-based therapy for celiac disease. The use of mass cytometry to gain detailed insight into the cellular basis for immune mediated gastrointestinal disorders and response to treatment modalities..

Cohesion within LUMC

There is close cooperation with other research sections in the IHB (Tregs, tetramers, HLA typing, ) and with clinical departments (haematology, nephrology, obstetrics, rheumatology, pathology, endocrinology, paediatrics, gastroenterology, various surgical departments) and related to clinical transplantation with Matchis (hematopoietic stem cell) and Eurotransplant (organ).