Late B lymphocyte action in dysfunctional tissue repair following kidney injury and transplantation

Cippà, Pietro E; Liu, Jing; Sun, Bo; Kumar, Sanjeev; Naesens, Maarten; McMahon, Andrew P.

doi:10.1101/343012

Cited by 24 publications

(28 citation statements)

References 64 publications

(48 reference statements)

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“…These changes in the relative composition of the B cell compartment could have consequences in the immune response against the allograft, as specific B cell signatures have been associated with transplant tolerance 7 and chronic kidney injury. 27 All kidney recipients in our cohort received the same immunosuppressive maintenance therapy, with tacrolimus, mycophenolate mofetil, and glucocorticoids, which did not allow us to discern the specific effect of each drug on the B cells. However, the decrease in transitional and IL-10 þ Breg cell frequencies post-transplantation is consistent with a Figure 4 | The circulating follicular helper T (cTfh)/interleukin (IL)-10 þ regulatory B (Breg) ratio increased post-transplantation (PosTx), and a higher increase in this ratio preceded biopsy-proven acute rejection (BPAR).…”

Section: Discussionmentioning

confidence: 99%

Imbalance favoring follicular helper T cells over IL10+ regulatory B cells is detrimental for the kidney allograft

Laguna‐Goya

Utrero‐Rico

Cano-Romero

et al. 2020

Kidney International

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A high frequency of regulatory B (Breg) cells, generally transitional B cells, has been associated with long-term kidney allograft survival and operational tolerance. However, circulating follicular helper T cells (cTfh) correlate with graft rejection. In order to better understand the interplay between these cell subsets and to determine their association with graft outcome we studied transitional and IL10 D Breg cells, as well as cTfh, pre-and posttransplantation in a prospective cohort of 200 kidney transplant recipients and in healthy volunteers. Patients with end-stage kidney disease had higher frequencies of transitional and IL10 D Breg cells compared to controls, and these subsets decreased during the one-year posttransplant follow-up. Higher frequencies of pre-transplant IL10 D Breg cells, and a larger reduction in these cells early post-transplantation, predicted acute rejection and graft failure. Moreover, IL10 D Breg cells correlated with cTfh pretransplantation, and a post-transplant increase in the cTfh/ IL10 D Breg ratio preceded acute rejection. Thus, evaluation of pre-transplant IL10 D Breg cells and the regular monitoring of the cTfh/IL10 D Breg ratio may be useful to assess post-transplant risk. Hence, our observations suggest the need to develop therapeutic strategies aimed at preserving regulatory B cells, and depleting Tfh, posttransplantation.

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Section: Discussionmentioning

confidence: 99%

Imbalance favoring follicular helper T cells over IL10+ regulatory B cells is detrimental for the kidney allograft

Laguna‐Goya

Utrero‐Rico

Cano-Romero

et al. 2020

Kidney International

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“…Recently, Cippa et al . suggested that kidney injury in ischemia/reperfusion injury and transplantation are both mediated by a B‐cell response to dysfunctional tissue repair. Interestingly, patients who developed chronic rejection already showed elevated B‐cell activities and other common gene signatures for acute kidney injury including genes related to fibrosis (e.g., COL1A1, DPT, and MMP7) and inflammation (e.g., CD52, CXCL10, and CCL21).…”

Section: The Role Of B Cells Beyond Antibodymentioning

confidence: 99%

B cells in transplant tolerance and rejection: friends or foes?

et al. 2019

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Our understanding of the role of B cells in organ transplantation remains incomplete and continues to grow. The majority of research has focused on the detrimental role of antibodies that drive the development of pathogenesis of the transplanted organ. However, it has been shown that not all donor-specific antibodies are harmful and in some circumstances can even promote tolerance through the mechanism of accommodation. Furthermore, B cells can have effects on transplanted organs through their interaction with T cells, namely antigen presentation, cytokine production, and costimulation. More recently, the role and importance of Bregs was introduced to the field of transplantation. Due to this functional and ontogenetic heterogeneity, targeting B cells in transplantation may bring undesired immunologic side effects including increased rejection. Therefore, the selective control of B cells that contribute to the humoral response against donor antigens will continue to be an important and challenging area of research and potentially lead to improved long-term transplant outcomes.

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“…In addition, IRI/DGF likely contributes to B cell activation and DSA development in human renal allografts. Cippa et al demonstrated a causal relationship between IRI/DGF and subsequent B cell activation in the allografts 45 . This clearly differed from allografts not experiencing IRI/DGF as no B cell signals were demonstrated on protocol biopsies.…”

Section: Therapeutic Approaches To Treatment Of Amrmentioning

confidence: 99%

Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection

et al. 2019

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Modification of pathogenic antibodies and their effector functions in autoimmune diseases or use of B cell/plasma cell‐directed anticancer therapies have illuminated the biologic relevance of B cells, plasma cells (PCs), and pathogenic antibodies and complement in alloimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines that drive dysfunctional immune responses. Current methods to reduce alloantibodies are only modestly successful. Rituximab is used for desensitization and antibody‐mediated rejection (AMR) treatment by targeting CD20 found on B‐lymphocytes. However, PCs do not express CD20, likely explaining the limited success of this approach. Intravenous immunoglobulin and plasmapheresis (PLEX) have limited success due to antibody rebound. Despite attempts to develop tolerable therapeutics for management of AMR, none, to date, have been universally accepted or obtained Food and Drug Administration approval. Lack of approved therapeutics often results in patients having a much shorter graft survival due to AMR. Repurposing drugs from autoimmunity and cancer immunotherapy has rapidly yielded important advancements in the care of AMR patients. Here we discuss emerging therapeutics aimed at prevention and treatment of AMR.

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Late B lymphocyte action in dysfunctional tissue repair following kidney injury and transplantation

Cited by 24 publications

References 64 publications

Imbalance favoring follicular helper T cells over IL10+ regulatory B cells is detrimental for the kidney allograft

Imbalance favoring follicular helper T cells over IL10+ regulatory B cells is detrimental for the kidney allograft

B cells in transplant tolerance and rejection: friends or foes?

Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection

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