Sacha De Serres | Laval University

Taking advantage of the High Interindividual Heterogeneity in the Expression of HLA molecules on Human Kidney Endothelial Cells to Personalize Immunotherapy

Co-Applicant(s):  Mohsen Agharazii

Lay Abstract

Using the heterogeneity in HLA expression between individuals to personalize the immunosuppression of kidney transplant recipients.

Background: Immunosuppression is essential for the treatment of kidney transplant recipients and patients with immune-mediated diseases. Unfortunately, patients taking immunosuppressants may experience undesirable side effects, the most important being serious infections and cancers. Currently, patients are mostly prescribed immunosuppressants in a “one size fits all” fashion, because it is difficult to determine the immune response of these patients. Transplant recipients face a difficult situation where they want to keep their graft healthy, but they also want to keep themselves healthy.

Purpose: We need to improve our knowledge on how to predict this immune response if we want to be successful at preventing these complications. In the last 10 years, we developed in my lab a cell-based assay that measures the capacity of the immune system. This assay can predict the risk of serious infections and cancer. Here we propose to add a new dimension to this tool by using the HLA information obtained before transplant in a novel manner. Ultimately what we aim is to deliver to the transplant community an integrated, multistep instrument to better assess the risk of undesirable effects of immunosuppression. These tools should help to adjust the immunosuppressants accordingly.

Method: As preliminary work, we recently demonstrated and published that there is a substantial variability between humans in the expression of the HLA molecules at the surface of endothelial cells. Moreover, we observed that this variability was predicted by the specific HLA genotype of each individual. Because the HLA molecules are responsible for the triggering of the immune response, their expression is crucial. Emerging studies in oncology have shown that the HLA genotype can be helpful to predict the response to immunotherapy. Here, we first propose to use a large multicenter, international cohort of kidney recipients to investigate the relationship between the HLA genotype and the occurrence of serious infections/cancers. Second, we propose to use biobanked cells from kidney recipients to measure their surface expression of HLA protein with a flow cytometer, in the lab. We will use this information to examine whether this level of HLA expression on the cells can also predict the occurrence of serious infections/cancers.

Anticipated outcomes: We anticipate that both the HLA genotype and the level of HLA protein expression will correlate with the occurrence with adverse events, in such a way that it will help to predict to determine whether the kidney transplant recipients are at low, moderate, or high risk of these events.

Patient engagement: The prediction tool is in a stage of development. Therefore, at this point we do not have patients involved in the study. If the results of the current study are conclusive, we will involve patients to better determine how this information will be interpreted by patients in the shared decision-making of the immunosuppression. In other words, we will want to determine to what extent the strength of the prediction would make the patients willing to modify their immunosuppression.

Relevance: The novelty of this project is that it deals with over-immunosuppression, a serious but underappreciated problem in transplantation. Lowering the immunosuppression will, to a certain extent increase the risk of rejection. However, the risk of rejection nowadays is very low, given the strong immunosuppression prescribed. Paradoxically, the mortality in kidney recipients is now driven more by adverse events than by rejection. What we want to achieve for the patients is to get a better balance between the benefits and the adverse effects of immunosuppression.

Conclusion: We may have reached a point where immunosuppression is sometimes more toxic than beneficial. Personalizing immunotherapy should help to get the benefits of transplantation while minimizing the occurrence of serious adverse events. This knowledge could be useful not only to kidney transplant recipients, but to any patient receiving immunosuppressants.