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In View: Research Highlights

Research Highlights

Anwar, Imran J. MD1; Luo, Xunrong MD, PhD2

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doi: 10.1097/TP.0000000000004225
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Human IL-10-producing B Cells Have Diverse States That Are Induced From Multiple B-cell Subsets

Glass MC, Glass DR, Oliveria JP, et al. Cell Rep. 2022;39:110728.

Regulatory B cells (Bregs) possess immunoregulatory properties through interleukin-10 (IL-10) secretion. IL-10+ B cells maintain and regulate immune homeostasis and have been implicated in a myriad of immune-related conditions.1 In clinical transplantation, Bregs have been linked to operational tolerance, a state in which recipients maintain stable graft function despite the lack of immunosuppression.2 A wide variety of Breg phenotypes have been characterized in clinical and experimental models.3 To date, however, there is no encompassing immunophenotypic signature to identify those cells in humans. This constitutes a major barrier to understanding and characterizing Bregs clinically. Furthermore, studies aimed at evaluating human IL-10+ B cells have been primarily conducted in disease states and require ex vivo stimulation to clearly distinguish IL-10+ B cells.

Recently published in Cell Reports, Glass et al4 performed high-dimensional characterization of IL-10+ B cells from healthy individuals and liver transplant recipients using mass cytometry. Compared with fluorescence-based cytometry, mass cytometry utilizes antibodies that are labeled with heavy metal tags.5 Samples are analyzed by time-of-flight mass spectrometry to simultaneously quantify the abundance of heavy metal isotypes. This avoids the interference from spectral overlap that commonly occurs in polychromatic flow cytometry and allows for characterization of >60 channels concurrently. The authors first evaluated strategies to generate IL-10+ B cells among peripheral blood mononuclear cells under various stimulatory conditions. They found that expansion was highly dependent on cytokine stimulation and activation environment, and optimized expansion (mean of 34.1% IL-10+ B cells) with TLR9 stimulation, CD40 activation, and the addition of several cytokines (IL-2, IL-21, IL-35). In all stimulatory conditions, IL-10+ B cells had a highly activated B-cell phenotype, yet no single immunophenotype captured all IL-10+ B cells populations. Previously reported Breg phenotypes were present following B-cell stimulation; however, this accounted for a low percentage of total IL-10+ B cells, suggesting that the majority of IL-10+ B cells were not accounted for by previously described B-cell subsets. Furthermore, stimulation produced IL-10+ B cells from all B-cell subsets (ie, memory, transitional, naïve). Next, the authors mapped the temporal dynamics of cytokine production and marker expression of B cells and IL-10+ B cells following stimulation under the aforementioned conditions and were unable to find a single surface maker uniquely defining IL-10+ B cells over time. Furthermore, proinflammatory cytokine expression (TNFα and IL-6) preceded IL-10 induction. Finally, IL-10+ B cells were assessed from liver transplant recipients. Operationally tolerant recipients had a significantly higher proportion of IL-10+ B cells and greater ratio of IL-10+:TNFα+ total B cells compared with recipient controls, accompanied by a corresponding increase in CD9 expression.

The current study advances our understanding of the human Breg population by providing a thorough immunophenotyping of IL-10+ B cells both in healthy individuals and liver transplant patients. Interestingly, there was not a single canonical subset of IL-10+ B cells detected; rather, human IL-10+ B cells form an impermanent subtype that is highly dependent on stimulation conditions and duration. In addition to providing an explanation for the myriad of human Breg subtypes previously described, these data suggest that a high-dimensional and polyfunctional approach is necessary to thoroughly assess the Breg population in humans. Intriguingly, this study suggests that Bregs might have a salutary effect not only in kidney transplantation but also in liver transplantation.

This study raises several important questions that are worth investigating in the future: (1) whether CD9 expression and the IL-10+:TNFα+ total B ratio could serve as markers for operational tolerance; (2) whether tissue-derived IL-10+ B cells also display similar heterogeneous phenotypes and polyfunctionality; and (3) whether similar findings hold true when assessing the profile of IL-10+ B cells in a larger human cohort.

Overall, the current study by Glass et al makes important progress and builds a foundation for future studies in this area.

De Novo Malignancies After Kidney Transplantation

Al-Adra D, Al-Qaoud T, Fowler K, et al. Clin J Am Soc Nephrol. 2022;17:434–443.

Cancer is the second leading cause of death among organ transplant recipients, with an excess risk approximately 2 to 3 times higher compared with an age- and sex-matched general population.1 Although explicit guidelines for risk reduction for cardiovascular disease as the leading cause of death posttransplant are provided for transplant recipients, cancer screening and prevention guidelines are much less clear.

In this review, Al-Adra et al2 summarized incidence, mortality, risk factors, screening, and management of de novo posttransplant malignancies in an evidenced-based fashion with up-to-date information. Cancer incidences, in comparison to age- and sex-matched general population, have an average 2- to 3-fold increase, with the greatest increase in viral-related and immune-driven cancers such as posttransplant lymphoproliferative disease (PTLD). Interestingly, breast and prostate cancers are among the few solid organ cancers whose incidences are not increased in transplant recipients. For cancer mortality, there is an average 5- to 10-fold increase, with the greatest incidence observed for melanoma, urogenital cancers, and non-Hodgkin’s lymphoma. The cause for increased cancer mortality is thought to be multifactorial, including a different cancer biology in transplant recipients and reduced attention to cancer screening and prevention. Cancer risk factors, specific to transplant recipients are the use of immunosuppression, particularly T cell–depleting agents, acute rejections, sensitization status, and duration of dialysis before transplantation. Among these, having chronic kidney disease (irrespective of the chronic kidney disease stage) is associated with higher cancer risks and poor cancer outcomes. Closely correlating to these risk factors are the putative mechanisms of cancer development after transplantation, including poor immune control of known oncogenic viruses, accumulation of DNA damage and mutations, increased level of transforming growth factor-beta, and incomplete T cell–recovery postdepletional induction. Geographic area-specific cancers are thought to be related to distinct regional dietary supplementations or endemic viral-related morbidities.

To implement appropriate cancer screening and management plans, the authors first reviewed the most common cancers in transplant recipients including renal cell carcinoma, skin cancers, and PTLD. Specifically related to transplantation, Kaposi’s sarcoma is associated with the use of calcineurin inhibitors and can be reduced and treated by mTOR inhibitors. PTLD is predominantly associated with Epstein-Barr virus infection and the use of costimulation blockade. The authors also present a specific set of recommendations for cancer screening in transplant recipients. For breast, prostate, bowel, cervical, lung, and liver malignancies, screening recommendations were similar to those for general population. For skin cancer screening, monthly self-examination and every 6–12 mo total body skin examination by dermatologists are recommended. For PTLD, routine monitoring of high-risk patients for Epstein-Barr virus by nucleic acid testing is recommended. As for the management after the diagnosis of cancer has been confirmed, judicious reduction of immunosuppression remains to be considered the best first step; although, the evidence on the amount by which immunosuppression could safely be reduced remains unknown. Furthermore, at this moment, the use of immune checkpoint inhibitors cannot be recommended because of the lack of evidence regarding therapeutic efficacy and the theoretical concern for rejection from nonspecific immune activation. Ultimately, the most appropriate management strategy is one that puts patients’ perspective at its center. This approach would require a multidisciplinary team including the patients themselves to address individual needs, and to design observational and interventional clinical trials that will ultimately provide the best evidence to support the long-term care of transplant recipients.

REFERENCES

1. Chekol Abebe E, Asmamaw Dejenie T, Mengie Ayele T, et al. The role of regulatory B cells in health and diseases: a systemic review. J Inflamm Res. 2021;14:75–84.
2. Peng B, Ming Y, Yang C. Regulatory B cells: the cutting edge of immune tolerance in kidney transplantation. Cell Death Dis. 2018;9:109.
3. Mauri C, Menon M. The expanding family of regulatory B cells. Int Immunol. 2015;27:479–486.
4. Glass MC, Glass DR, Oliveria JP, et al. Human IL-10-producing B cells have diverse states that are induced from multiple B cell subsets. Cell Rep. 2022;39:110728.
5. Hartmann FJ, Bendall SC. Immune monitoring using mass cytometry and related high-dimensional imaging approaches. Nat Rev Rheumatol. 2020;16:87–99.

REFERENCES

1. Au EH, Chapman JR, Craig JC, et al. Overall and site-specific cancer mortality in patients on dialysis and after kidney transplant. J Am Soc Nephrol. 2019; 30:471–480.
2. Al-Adra D, Al-Qaoud T, Fowler K, et al. De novo malignancies after kidney transplantation. Clin J Am Soc Nephrol. 2022;17:434–443.
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