Hierarchy of Human B Cell Regeneration after Rituximab Therapy.

Constant immunoglobulin levels throughout life-time may be maintained by either long lived plasma cells or continuous formation of immunoglobulin secreting cells (ISC). Rituximab therapy targets CD20+ B cells, thus selectively spares B progenitor cells and plasma cells, providing an in vivo model to investigate human B cell homeostasis.

After weekly administration of rituximab in patients with follicular lymphoma, peripheral blood B cells are virtually absent (<0,01%), and no ISC are detected. In contrast, during rituximab maintenance therapy (administered in two months intervals) small numbers of B cells can be detected. These carry the phenotype of new formed plasma blasts (CD27++/CD38++/icIg+++ and Ki67+) and are identified as ISC in ex vivo ELISPOT assay.

Surprisingly, ISC detected in treated patients were the same as in healthy donors in absolute numbers, while B cells were still reduced by 100-fold. Only 4 to 6 months after therapy human naive and memory B cells were detected in peripheral blood again. Thus, regeneration of human peripheral blood B lymphocytes follows a hierarchy: Recirculating ISC recover rapidly to normal steady state levels, while B cells with naive or memory phenotype require longer time periods. This hierarchy may represent two elements within the B cells system: a primary system sustaining constant antibody levels and a secondary system providing a diverse repertoire for adaptive immune responses.