Abstract
We aimed to investigate the mechanisms of humoral immune activation in ABMR using a MHC-mismatched rat kidney transplant model. We applied low dose cyclosporine A (loCNI) to allow donor-specific antibody (DSA) formation and rejection and high dose cyclosporine A (hiCNI) for non-rejection. DSA and leukocyte subsets were measured by flow cytometry. Germinal centers (GC), T follicular helper cells (Tfh), plasma cells and interleukin-21 (IL-21) expression were analyzed by immunofluorescence microscopy. Expression of important costimulatory molecules and cytokines was measured by qRT-PCR. Allograft rejection was evaluated by a nephropathologist. We found that DSA formation correlated with GC frequency and expansion, and that GC size was linked to the number of activated Tfh. In hiCNI, GC and activated Tfh were virtually absent, resulting in fewer plasma cells and no DSA or ABMR. Expression of B cell activating T cell cytokine IL-21 was substantially inhibited in hiCNI, but not in loCNI. In addition, hiCNI showed lower expression of ICOS ligand and IL-6, which stimulate Tfh differentiation and maintenance. Overall, Tfh:B cell crosstalk was controlled only by hiCNI treatment, preventing the development of DSA and ABMR. Additional strategies targeting Tfh:B cell interactions are needed for preventing alloantibody formation and ABMR.
Highlights
Antibody-mediated rejection (ABMR) is a major cause of allograft failure in kidney transplantation (Ktx) [1]
Using this model closely resembling human Ktx, we investigated the relationship between germinal center (GC), T follicular helper cells (Tfh) and Donor-specific antibodies (DSA) formation in secondary lymphoid organs (SLO) and the effects of CNI dose variation on key effector cells and molecules
We found that DSA formation and ABMR development were prevented in rats treated with hiCNI, while loCNI treatment did not hinder DSA formation and only partially prevented ABMR
Summary
Antibody-mediated rejection (ABMR) is a major cause of allograft failure in kidney transplantation (Ktx) [1]. Donor-specific antibodies (DSA) are responsible for initiating ABMR and their serological presence, whether pre-existing or formed after transplantation (“de novo”), is associated with poorer graft survival [2,3,4,5,6]. Antigen-specific B cells undergo somatic hypermutation (SHM) of their immunoglobulin (Ig) genes and perform class switch recombination (CSR) to generate affinity-matured antibodies with specific effector functions [7]. Certain clinical observations suggest that processes integral to the GC reaction control the development of ABMR. The affinity maturation and Ig (sub-) class switch of DSA, which are regulated in the GC reaction, impact the development and course of ABMR
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