Unwanted antibody responses arising from pathological B-cell responses underlie many diseases. Non-specific immunosuppression remains the frontline therapy, and induction of antigen-specific tolerance remains elusive. Immunotherapies typically manipulate the T-cell component of pathogenic immune responses but few directly target B cells. Transfer of gene-engineered hematopoietic stem cells (HSC) is an approach endowed with features that engender great promise for antigen-specific immunotherapy, particularly the potential to deliver antigen in a form directly tolerogenic to B cells. However this approach must be used in a way that preserves bystander immunity.
Gene-engineered bone marrow encoding ubiquitous ovalbumin (OVA) expression was transferred after low-dose (300cGy) immune-preserving irradiation. Homeostasis of pre-existing OVA-specific B cells and those arising after BM transfer was monitored using flow cytometry and responsiveness to immunisation was tested. OVA-specific B cells were purged from the pre-exiting mature B-cell population in recipients following transfer of OVA-encoding BM as well as from newly-developed B cells that arose after BM transfer. OVA-specific antibody production was largely prevented after OVA-encoding BM transfer and this was consequent to inhibition of B-cell activation, development of germinal centres and plasmablast differentiation. Low levels of gene-engineered bone marrow chimerism (~20%) were sufficient to limit antigen-specific antibody production. These data show that antigen-specific B cells within an established B cell repertoire are susceptible to de novo tolerance induction and this can be mediated by transfer of gene-engineered bone marrow.
This study provides an important proof-of-principle that HSC-mediated gene therapy has the capacity to modulate a mature developed B-cell repertoire under conditions where bystander immunity is preserved.