Human Mesenchymal Stem Cells Inhibit In Vitro Antibody Production Against Alloantigens.

Abstract

Antibodies directed against alloantigens are implicated in the pathogenesis of several immune reactions complicating transplantation. In particular, this humoral response unfavorably affects the outcome of solid organ transplantation, and it has been hypothesized to be responsible for some of the clinical manifestations related to graft-versus-host disease (GVHD). In detail, the presence of antibodies against donor cells is a contraindication to kidney transplantation because of the risk of hyperacute rejection. In the effort to expand the donor pool, trials of allograft transplantation across HLA-sensitization have been conducted by means of strategies including pre-transplant plasmapheresis, intravenous immunoglobulins (Ig), anti-B cell monoclonal antibodies and splenectomy, associated with high-intensity immunosuppressive regimens. These measures have proved only partially successful in preventing humoral rejection in high-risk patients. Thus, the development of new therapeutic tools able to blunt alloantibody production could be a welcomed implementation to existing protocols. Mesenchymal stem cells (MSC) have been demonstrated to possess immunomodulatory capacity, since they induce T-cell hyporesponsiveness in vitro, prolong survival of skin graft in a primate model, and seem to decrease GVHD incidence and severity in humans given hematopoietic stem cell transplantation.To verify whether MSC may exert an inhibitory effect on antibody production, we stimulated B-cell-enriched peripheral blood mononuclear cells (PBMC) obtained from healthy controls (n=9) or sensitized prospective kidney recipients (n=5) in a mixed lymphocyte culture (MLC) against irradiated HLA-disparate stimulator PBMC (controls) or stimulators cells bearing HLA antigens matched with the positive cross-match (patients). Antibody production in the absence or in the presence of third-party allogeneic MSC (responder:MSC ratio:4:1) was then evaluated by ELISA. We found that the addition of MSC at the beginning of MLC considerably inhibited IgG and IgM production (median fold-decrease of IgG production: controls, 7; patients, 5; median fold-decrease of IgM production: controls, 17; patients, 4). Our preliminary findings indicate that third-party MSC are able to suppress antibody production in vitro, and may therefore help to overcome a positive cross-match in sensitized transplant recipients. These results may also contribute to partly explain the mechanism at the basis of the favourable effect played by MSC in patients with GVHD.