Commentary
Preventing Memory B Cell Formation: A Story of Mice and Men? Sebastiaan Heidt, PhD1 and Frans HJ. Claas, PhD1
W
ithin transplant immunology, humoral immunity has gained much interest in the last couple of years. Many functions have been attributed to B cells, including antibody production, antigen presentation, tertiary lymphoid organ formation, as well as positive and negative regulation of immune responses by cytokine production. All of these functions may be of importance in the immune response against allogeneic tissues and require detailed investigation. However, the difficulty in studying B cells in the transplant setting has been the inability to track and quantify alloantigen-specific B cells. Fortunately, the development of recombinant MHC class I molecules, and more recently of MHC class II molecules, has allowed for studies on the formation of donor-specific B-cell responses. In this issue of Transplantation, Yang and colleagues1 describe for the first time the use of MHC class II tetramers to track the fate of I-Ed-specific B cells upon immunization and/or transplantation in a mouse model. Upon immunization, either by donor splenocyte infusion or a heterotopic heart transplant, they found a significant increase in the number of I-Ed–specific B cells in draining lymph nodes or spleen, half of which displayed a germinal center (GC) phenotype. In contrast, up on heart transplantation in previously sensitized mice, a minority of I-Ed–specific B cells acquired a GC phenotype. This secondary challenge did induce a much more robust antibody response compared to a primary heart transplant, as shown by I-Ed-specific enzyme-linked immunospot analysis. Alloantigen-specific B cells rely on crosstalk with T cells to become fully activated, and may therefore be (partially) suppressed by current immunosuppressive regimens. Along this line, costimulation blockade by CTLA4-Ig may also influence B cell responses. Indeed, the same group had already shown in mouse models that CTLA4-Ig was effective at inhibiting MHC class I-specific B cell responses.2 In their current paper, Yang et al1 use an elegant system to track donor specific memory B cell generation. By determining the time frame of sensitivity to CTLA4-Ig (abatacept) treatment, the authors were
Received 2 March 2016. Accepted 4 March 2016. 1
Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. The authors declare no funding or conflicts of interest. S.H. and F.H.J.C. wrote the article. Correspondence: Sebastiaan Heidt, PhD, Leiden University Medical Center Dept. of Immunohaematology and Blood Transfusion Albinusdreef 2-2333 ZA Leiden, the Netherlands. (
[email protected]). Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/16/10008-1605 DOI: 10.1097/TP.0000000000001254
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able to show that B-cell memory developed within the first 2 weeks after transplantation. After this period, CTLA4-Ig treatment was ineffective, resulting in the formation of B-cell memory. Concomitantly, donor-specific antibody (DSA) formation was diminished if CTLA4-Ig treatment was initiated within the first 2 weeks after primary immunization. The latter results are in concert with previous research showing that costimulation blockade may be an effective means of preventing DSA formation and antibody-mediated rejection. Kim et al3 showed in a primate kidney transplant model that both interference with the CD40-CD40L pathway, as well as the CTLA4–B7-1/B7-2 pathway (belatacept) led to disturbance of the GC response, leading to the abrogation of DSA production. The maintenance of a relatively high level of IgM+ B cells under costimulation blockade suggested an arrest in isotype switching. From a recent update of the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial study on the use of belatacept in the clinical setting, it is clear that the occurrence of DSA formation is markedly lower in patients receiving belatacept, as compared with patients receiving a cyclosporin-based immunosuppression regimen.4 Whether DSA of the IgM isotype are present in these patients has not yet been investigated. A striking finding in the current paper by Yang and colleagues1 is that costimulation blockade, besides abrogating DSA formation, also hampers the formation of memory B cells, even when the alloimmune response has already commenced. This may be an important observation, partially explaining why in the clinical setting the formation of DSA is scarce in patients receiving costimulation blockade-based immunosuppression. The next step will be to investigate the fate of donor-specific B cells under costimulation blockadebased immunosuppression in the clinical setting. Several tools are now available to make this possible, also in humans. Even before the use of MHC tetramers for tracking B cells in mouse models, HLA tetramers had already been used for the quantification and purification of HLA-specific B cells from pregnancy immunized individuals,5 as well as in the clinical transplantation setting.6 More recently, ELISPOT assays for the detection of HLA-specific memory B cells have been developed, both for HLA class I,7 as well as for HLA class II.8 Importantly, in sensitized patients, it has been shown that HLA class I– and II–specific memory B cells are present in the circulation,7,9 and that these memory B cells may even be present in the absence of the accompanying serum antibody specificities.10 It will be of great interest to determine what will happen to the (preexisting) human donor-specific memory B-cell repertoire in patients receiving a kidney transplant under costimulation blockade-based immunosuppression. Techniques using recombinant MHC molecules will be pivotal to perform such studies. Based on the data from Yang and colleagues,1 www.transplantjournal.com
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prevention of the formation of donor-specific memory B cells in the clinical setting may be on the horizon. REFERENCES 1. Yang J, Chen J, Young J, et al. Tracing donor-MHC Class II reactive B cells in mouse cardiac transplantation: delayed CTLA4-Ig treatment prevents memory alloreactive B cell generation. Transplantation. 2016; 100:1683–1691. 2. Chen J, Yin H, Xu J, et al. Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig. Am J Transplant. 2013;13: 2280–2292. 3. Kim EJ, Kwun J, Gibby AC, et al. Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection. Am J Transplant. 2014;14:59–69. 4. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016;374:333.
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5. Mulder A, Eijsink C, Kardol MJ, et al. Identification, isolation, and culture of HLA-A2-specific B lymphocytes using MHC class I tetramers. J Immunol. 2003;171:6599. 6. Zachary AA, Lucas DP, Montgomery RA, et al. Rituximab prevents an anamnestic response in patients with cryptic sensitization to HLA. Transplantation. 2013;95:701–704. 7. Heidt S, Roelen DL, de Vaal YJ, et al. A novel ELISPOT assay to quantify HLA-specific B cells in HLA-immunized individuals. Am J Transplant. 2012;12:1469. 8. Karahan GE, de Vaal YJ, Roelen DL, et al. Quantification of HLA class II-specific memory B cells in HLA-sensitized individuals. Hum Immunol. 2015;76:129. 9. Lucia M, Luque S, Crespo E, et al. Preformed circulating HLA-specific memory B cells predict high risk of humoral rejection in kidney transplantation. Kidney Int. 2015;88:874. 10. Snanoudj R, Claas FH, Heidt S, et al. Restricted specificity of peripheral alloreactive memory B cells in HLA-sensitized patients awaiting a kidney transplant. Kidney Int. 2015;87:1230.
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