Importance of B cells to development of regulatory T cells and prolongation of tissue allograft survival in recipients receiving autologous bone marrow transplantation

Abstract

We previously showed that congenic bone marrow transplantation (BMTx) post myeloablation augmented tissue allograft survival in association with increased regulatory T (Treg) cells of both host and bone marrow donor origin. Regulatory B (Breg) cells can also modulate T-cell immunity and B cells may be implicated in the development of Treg cells. Accordingly, we explored the effect of B-cell depletion in vivo on augmented graft survival post BMTx. C57BL/6 mice received BALB/c skin allografts followed 7 days later by myeloablation using cyclophosphamide and busulphan. Mice then received T-cell-depleted bone marrow from CD45.1 congenic donors, and ongoing immunosuppression with rapamycin (to day 28 after BMTx). Control mice received cyclophosphamide and busulphan followed by rapamycin, but not congenic bone marrow. At different times post BMTx, mice received B-cell-depleting antibody treatment, and the effect on both skin graft survival, and induction of Treg cells was assessed. BMTx resulted in significantly prolonged skin graft survival versus control mice, in association with attenuated donor-specific alloreactivity relative to controls, increased splenic Treg cells and significantly diminished anti-donor IgG. In mice receiving infusion of B-depleting antibodies for 12 days from day 15 post BMTx, both graft survival and Treg cell activity were diminished, particularly for functional Treg cells of donor origin. Adoptive transfer of Breg cells from mice harvested at 15 days post BMTx prolonged survival in naive transplanted mice and increased Treg cell levels. Thus, autologous BMTx augmentation of graft survival is dependent in part upon a population of Breg cells that can modulate the function of donor-derived Treg cells.

Mechanism(s) of prolonged attenuation of allergic responses after modulation of idiotypic regulatory network

“…Our data show that depletion of both CD4 + and CD8 + T cells post administration of anti-idiotype and immune Ig abolishes the suppression seen-the effect was most marked with combined CD4 and CD8 depletion. Most interestingly, using mAbs shown elsewhere to expand CD25 + Treg [22, 25, 26], we document increased suppression of Th2 responses by infusion of these mAbs after first commencing treatment with anti-idiotype and immune Ig. We suggest these data reflect an important role for perturbation of immune regulatory networks using homologous or heterologous anti-idiotype Ig and immune Ig in suppression of Th2 immunity, and thus potentially allergic responses, in naïve and sensitized hosts.…”

“…We [25, 26] and others [22, 28] have suggested that antibodies made against a molecule, TNFRSF25, expressed at the cell surface of CD4 + CD25 + Tregs may augment immunoregulation by putative Tregs in vivo-at least one such study has reported this molecule enhanced regulation of allergic immunity [22]. We have reported on production of several rat mAbs to a peptide of TNFRSF25 common to both the human and mouse molecules and observed by FACS and ELISA (with plate-bound cells) significant binding of several mAbs to enriched CD4 + Tregs.…”

Progress in Liver Transplant Tolerance and Tolerance-Inducing Cellular Therapies

“…At present, autologous HSCT has also been widely used in various types of liver cirrhosis, improving liver function in varying degrees ( 106 – 109 ). Coupled with the study of transplant animal models, these studies provide abundant theoretical basis for expanding autologous HSCT application in organ transplantation ( 110 – 112 ).…”

Regulatory B cells: Development, phenotypes, functions, and role in transplantation

“…105 In another study, depletion of total B cells before the establishment of EAE lead to exacerbated disease symptoms, but adoptive transfer of splenic IL-10-producing B cells before EAE induction normalized the disease progression, suggesting that these cells had a protective role in the onset of this central nervous system (CNS) pathology. 108 The direct engagement of CD1d high CD5 + B10 with Tregs through CD5 and CD72 has shown to induce their expansion and homeostasis. 106 In a murine model of rheumatoid arthritis (RA) induced by methylated BSA in mice deficient in Wiskott-Aldrich syndrome protein (WASp), which is characterized by exacerbated inflammatory activity and reduced Treg and Breg populations along with an increased number of Th17 inflammatory lymphocytes, the adoptive transfer of Bregs isolated from WT mice was able to restore the balance.…”

“…107 In a different animal model of congenic bone marrow transplantation (BMTx), in vivo adoptive transfer of B cells after myeloablation showed increased allograft survival through donor-specific Treg development. 108 The direct engagement of CD1d high CD5 + B10 with Tregs through CD5 and CD72 has shown to induce their expansion and homeostasis. 109 In turn, Tregs were able to induce the expansion of IL-10-producing B cells through reciprocal interactions with the same two molecules.…”