Making a B-Line for Transplantation Tolerance (2011)

The authors discuss the findings by Le Texier et al (page 429) that B lymphocytes contribute to the development of tolerance in an experimental transplant model and their potential clinical implications. The authors discuss the findings by Le Texier et al (page 429) that B lymphocytes contribute to the development of tolerance in an experimental transplant model and their potential clinical implications. For over four decades B cells have been recognized as important components of the immune response to transplanted organs. Historically, interest in B cells has focused primarily on the production of pathogenic alloantibodies. However, two recent studies of tolerant human renal transplant recipients reported increased numbers of B cells compared to recipients with stable function receiving immunosuppression (1Newell KA Asare A Kirk AD et al.Identification of a B cell signature associated with renal transplant tolerance in humans.J Clin Invest. 2010; 120: 1836-1847Crossref PubMed Scopus (565) Google Scholar,2Sagoo P Perucha E Sawitzki B et al.Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans.J Clin Invest. 2010; 120: 1848-1861Crossref PubMed Scopus (443) Google Scholar). In a third study, clinically tolerant renal transplant recipients were reported to display increased numbers of peripheral B cells with memory phenotypes defined as CD19+IgD−CD38+/−CD27+and inhibitory profiles based on a decreased ratio of the activating to inhibiting Fc receptors CD32a and CD32b (FcγRIIA/FcγRIIB) and increased BANK1, CD1d and CD5 (3Pallier A Hillion S Danger R et al.Patients with drug-free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype.Kidney Int. 2010; 78: 503-513Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). In nonhuman primates transiently depleted of B and T cells and maintained on sirolimus, long-term survival of allogeneic islets was associated an enrichment of nonisotype-switched immature and transitional B cells (CD19+CD27−CD38+IgM−). In contrast, rejecting recipients that received the same treatment reconstituted their B-cell repertoire with isotype-switched mature activated B cells (CD19+CD27+CD38+IgM−) (4Liu C Noorchashm H Sutter JA et al.B lymphocyte-directed immunotherapy promotes long-term islet allograft survival in nonhuman primates.Nat Med. 2007; 13 (Epub 2007 Oct 28.): 1295-1298Crossref PubMed Scopus (132) Google Scholar). These emerging clinical and preclinical data suggest that tolerance may be associated with alterations of the B-cell repertoire, although it must be noted that consensus as to the specific phenotype or maturation status of B cells in the setting of tolerance is lacking. These observations emphasize the need for further investigations of B cells in transplantation tolerance. Observations of altered B cells in tolerant recipients can be interpreted as an epiphenomenon, as a consequence of the absence of immunosuppression or even as expansion of residual alloaggressive B cells that may be deleterious. A contrary but compelling hypothesis is that B cells are primary drivers of the tolerant state. This hypothesis challenges the prevailing paradigm that regulatory T cells (Tregs) are the principal mediator of transplantation tolerance and is consistent with emerging data on the role of regulatory B cells (Breg) in other immune processes. In this issue of the American Journal of Transplantation Le Texier et al. report the results of a study designed to further address the role of B cells in tolerance. Using a model of heart transplantation in rats, tolerance was induced by treatment with LF15–0195, a deoxyspergualine analog. The major findings reported in this article are that B cells accumulate in organized germinal centers in the allografts and blood of tolerant recipients and that these B cells are blocked in their switch from IgM to IgG. Furthermore, they display an inhibitory phenotype as characterized by increased expression of FcγR2b relative to its activating counterpart FcγR2a. Tolerant recipients were also characterized by increased amounts of IgG1 and decreased amounts of IgG2b deposited in the allograft and circulating in the blood suggesting the existence of functional differences between B cells from tolerant recipients and nontolerant recipients. Furthermore, donor-specific antibodies from tolerant recipients resulted in a pattern of donor-type endothelial cell activation in vitro that was characterized by increased expression of the cytoprotective molecules HO-1, NOTCH-4 and CLEC-1 relative to donor-specific antibodies from nontolerant recipients. Finally, purified splenic B cells from tolerant recipients were able to transfer tolerance, demonstrating the presence of B cells with dominant regulatory properties. A role for B cells with regulatory properties in autoimmunity, infectious diseases and cancer is becoming increasingly more apparent (reviewed in Ref. 5Mauri C Blair PA Regulatory B cells in autoimmunity: Developments and controversies.Nat Rev Rheumatol. 2010; 6: 636-643Crossref PubMed Scopus (152) Google Scholar). Early reports of suppressor-inducer B cells that induced suppressor T cells in the early 1980s formed the basis for more detailed studies in the 2000s that demonstrated a role for B cells in regulating autoimmunity. At this time the lack of a marker identifying these regulatory B cells (analogous to FoxP3 for Treg) has limited our understanding of their ontogeny and defied their identification based on phenotypic markers. Nonetheless, IL-10 has emerged as being essential to the function of regulatory B cells. Because many different myeloid and lymphoid cells produce IL-10, it is unclear why IL-10 produced by B cells is critical for the control of adaptive immune responses. Interaction between Bregs and effector T cells at specific sites of inflammation or within secondary lymphoid organs may underlie a nonredundant role for regulatory B cells in controlling adaptive immune responses. Another possibility is suggested by the observation that B cells are potent inducers of CD4+ regulatory T cells (6Mauri C Ehrenstein MR The ‘short’ history of regulatory B cells.Trends Immunol. 2008; 29: 34-40Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar). The study of B cells in transplantation tolerance is currently in its infancy and, as such, much remains unknown. For instance, it remains uncertain whether tolerance can be reliably diagnosed by detection of increased numbers of B cells with a specific phenotype or maturational status. Are Bregs a developmentally defined lineage or are they induced, and if the latter, what are the factors that favor the development of Bregs in transplantation tolerance? The mechanisms by which B cells might facilitate long-term acceptance of organ allografts also require elucidation. Bregs may suppress alloimmune responses by mechanisms similar to those described in autoimmunity, namely through the production of IL-10 or through interactions with other regulatory components of the adaptive immune system, including Tregs. In this regard it is interesting to note that the Nantes group had previously reported that Tregs were increased in the same model of tolerance, and that CD4+ T cells could also transfer tolerance (7Chiffoleau E Beriou G Dutartre P Usal C Soulillou JP Cuturi MC Role for thymic and splenic regulatory CD4+ T cells induced by donor dendritic cells in allograft tolerance by LF15–0195 treatment.J Immunol. 2002; 168: 5058-5069Crossref PubMed Scopus (95) Google Scholar). Understanding the relative roles of Treg and Breg in this model will be crucial. Do Bregs and Tregs act synergistically or sequentially? Is the development of one dependent on the development of the other? In conclusion, despite current enthusiasm for Bregs as a mechanistic explanation for the observed alterations in the B-cell repertoire during transplantation tolerance, definitive evidence is still lacking. Furthermore, published reports of tolerant liver transplant recipients failed to identify significant differences between B cells in tolerant and nontolerant recipients suggesting organ-specific differences in the role of Breg in tolerance (8Martinez-Llordella M Lozano JJ Puig-Pey I et al.Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients.J Clin Invest. 2008; 118: 2845-2857PubMed Google Scholar). Thus, much remains to be done to define those situations in which B cells play a role in transplantation tolerance, the mechanisms by which they operate, how they interact with other components of the immune system and how to best promote their development. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.