Role of B-cell memory on CD38-targeting Human Leukocyte Antigen desensitization therapy in Highly sensitized kidney transplant candidates
[eng] INTRODUCTION: Kidney transplantation stands as the best treatment for end-stage renal disease (ESRD), offering superior outcomes in comparison to any type of dialysis therapY. The benefits of kidney transplantation include increased life expectancy, improved quality of life by eliminating the...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/215600 |
| Acceso en línea: | https://hdl.handle.net/2445/215600 http://hdl.handle.net/10803/692281 |
| Access Level: | acceso abierto |
| Palabra clave: | Immunologia Trasplantament renal Cèl·lules B Antígens Immunology Kidney transplantation B cells Antigens |
| Sumario: | [eng] INTRODUCTION: Kidney transplantation stands as the best treatment for end-stage renal disease (ESRD), offering superior outcomes in comparison to any type of dialysis therapY. The benefits of kidney transplantation include increased life expectancy, improved quality of life by eliminating the need for regular dialysis treatments and lower risk of complications, such as reduction of cardiovascular diseases, which are a major cause of mortality in ESRD patients. Overall, kidney transplantation not only offers a better quality of life but also reduces medical costs associated with long-term dialysis treatments. Unfortunately, only a small percentage of patients with ESKD receive a kidney transplant, being most barriers to access kidney transplantation patient-related, physician/providerrelated, and system-related. Still, beyond these healthcare system barriers, transplantation also faces some important limitations including the shortage of òrgans for all patients waitlisted and the lack of significant improvement of long-term graft survival rates, mainly due to activation of the alloimmune response leading to chronic (B-cell mediated) allograft rejection, calcineurin-inhibitors(CNI)-related nephrotoxicity, relapse of primary ESRD as well as the death of the patients with a functioning graft because of adverse events directly associated to chronic immunosuppression such as cancer and opportunistic infections and off-target effects related side effects inducing diabetes, hypertension, dyslipidemia that significantly increase the risk of fatal cardiovascular events. HYPOTHESIS: The hypothesis of this thesis is that considering the observed efficacy of anti-CD38 mAb to successfully deplete malignant cells in multiple myeloma patients, we hypothesize that anti-CD38 mAbs may target LLPCs and plasma cells also in highly sensitized transplant candidates, depleting one of the main production sources of anti-HLA antibodies leading to their elimination and increasing the probability of these patients to find an HLA compatible donor. Additionally, the assessment of the B-cell profile of each patient prior to therapy using high dimensional analysis with high-throughput technologies such as spectral flowcytometry, could identify specific biological features associated to a successful serological response to this therapy. Moreover, a thorough assessment of different cell sources of HLA-sp antibodies such as bone marrow-residing plasma cells, MBCs and serum antibodies in the context of patients undergoing desensitization with CD38-targeting therapy would provide deep insight on the immune mechanisms of allosensitization. OBJECTIVES The main objectives of this thesis are the following: •Assess the safety, pharmacokinetics and preliminary efficacy of the anti-CD38 mAb isatuximab in a phase 1/2 desensitization clinical trial (NCT04294459) in HS patients awaiting kidney transplantation. •Assess the biological effect of CD38-targeting therapy on peripheral blood and bone marrow B-cell subsets using phenotypical and functional immune assays. •Assessing the biological interplay of distinct HLA-sp immune memory compartments leading to serological sensitization •Investigate whether specific biological features of peripheral B-cell components prior to anti-CD38 therapy could discriminate between patients displaying successful serological responses from those showing low or no response to this therapy. •Validate these findings in an external, independent cohort of highly sensitized kidney transplant candidates receiving a different anti-CD38 mAb as desensitization therapy. |
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