Patients with drug-free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype

Abstract

Several transplant patients maintain stable kidney graft function in the absence of immunosuppression. Here we compared the characteristics of their peripheral B cells to that of others who had stable graft function but were under pharmacologic immunosuppression, to patients with chronic rejection and to healthy volunteers. In drug-free long-term graft function (DF) there was a significant increase in both absolute cell number and frequency of total B cells; particularly activated, memory and early memory B cells. These increased B-cell numbers were associated with a significantly enriched transcriptional B-cell profile. Costimulatory/migratory molecules (B7-2/CD80, CD40, and CD62L) were upregulated in B cells; particularly in memory CD19(+)IgD(-)CD38(+/-)CD27(+) B cells in these patients. Their purified B cells, however, responded normally to a polyclonal stimulation and did not have cytokine polarization. This phenotype was associated with the following specific characteristics which include an inhibitory signal (decreased FcgammaRIIA/FcgammaRIIB ratio); a preventive signal of hyperactive B-cell response (an increase in BANK1, which negatively modulates CD40-mediated AKT activation); an increased number of B cells expressing CD1d and CD5; an increased BAFF-R/BAFF ratio that could explain why these patients have more peripheral B cells; and a specific autoantibody profile. Thus, our findings show that patients with DF have a particular blood B-cell phenotype that may contribute to the maintenance of long-term graft function.

Preserving the B-Cell Compartment Favors Operational Tolerance in Human Renal Transplantation

“…Our quantitative data corroborate previous works in which OT presented similar percentage and absolute numbers of circulating B cells to HI individuals (13,19,20), although the authors often refer to the OT group as displaying increased numbers of circulating B cells (19). The state of OT does not seem to induce a global expansion of total circulating B cells or any of their subpopulations, but rather involves the quantitative maintenance of B cells similar to that observed in HI.…”

“…It was reported that kidneytransplanted OT individuals present preserved numbers of total (19,20), naive (20) and memory B cells (19,20) …”

Central Role of CD45RA− Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance

“…We and others previously reported an increased number of B cells 4 and the overexpression of numerous genes related to the proliferation, maturation, and differentiation of these cells. [5][6][7][8] In parallel, some studies, including ours, also suggest a potential role for regulatory T cells (Tregs) in these patients, with overexpression of several genes associated with regulatory functions. 6,[8][9][10] In particular, stable patients and recipients with ongoing chronic rejection display lower levels and proportions of CD4 + CD25 + Foxp3 + T cells compared with operationally tolerant patients and healthy volunteers.…”

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

“…hi B cells (a subset that has previously been associated with operational tolerance 43,44 ) are increased in patients on belatacept compared with controls on CNIs. 90 Most of the clinical data where belatacept was used come from two multinational phase 3 studies: the BENEFIT Trial and the BENEFIT-EXT Trial.…”

“…42 Interestingly, in organ transplantation, the composition of the B cell compartment is repeatedly identified as an important determinant for graft outcome. 43,44 Heidt et al 42 suggested that lymphocyte depletion with alemtuzumab may skew the B cell compartment toward a protolerogenic profile. This hypothesis has been further strengthened by another work that showed that a significant expansion of regulatory-type B cells (defined as CD19 + CD5 + CD1d high ) is associated with superior graft function and that this pattern is more common after alemtuzumab induction.…”