Effective treatment against severe graft-versus-host disease with allele-specific anti-HLA monoclonal antibody in a humanized mouse model

Abstract

Graft-versus-host disease (GVHD), mediated by donor-derived alloreactive T cells, is a major cause of nonrelapse mortality in allogeneic hematopoietic stem cell transplantation. Its therapy is not well-defined. We established allele-specific anti-human leukocyte antigen (HLA) monoclonal antibodies (ASHmAbs) that specifically target HLA molecules, with steady death of target-expressing cells. One such ASHmAb, against HLA-A*02:01 (A2-kASHmAb), was examined in a xenogeneic GVHD mouse model. To induce fatal GVHD, non-irradiated NOD/Shi-scid/IL-2Rγ(null) mice were injected with healthy donor human peripheral blood mononuclear cells, some expressing HLA-A*02:01, some not. Administration of A2-kASHmAb promoted the survival of mice injected with HLA-A*02:01-expressing peripheral blood mononuclear cells (p < 0.0001) and, in humanized NOD/Shi-scid/IL-2Rγ(null) mice, immediately cleared HLA-A*02:01-expressing human blood cells from mouse peripheral blood. Human peripheral blood mononuclear cells were again detectable in mouse blood 2 to 4 weeks after A2-kASHmAb administration, suggesting that kASHmAb may be safely administered to GVHD patients without permanently ablating the graft. This approach, different from those in existing GVHD pharmacotherapy, may open a new door for treatment of GVHD in HLA-mismatched allogeneic hematopoietic stem cell transplantation.

Increased splenic human CD4+:CD8+ T cell ratios, serum human interferon-γ and intestinal human interleukin-17 are associated with clinical graft-versus-host disease in humanized mice

“…Of note, histological evidence of GVHD was more apparent in humanized mice with clinical GVHD compared to those with subclinical GVHD. The reduced histological GVHD in mice with subclinical GVHD is similar to that observed in the livers [33,34,36,37] and small intestine [33,38] of humanized mice following various treatments to prevent GVHD. To this end, the current study provided the opportunity to examine differences in humanized mice with subclinical versus clinical GVHD, and to determine factors that correspond with clinical GVHD development.…”

Single blood transfusion induces the production of donor-specific alloantibodies and regulatory T cells mainly in the spleen

“…Nakauchi et al (27) reported that anti-donor class I HLA allele-specific mAbs selectively suppress GvHD following allogeneic hematopoietic stem cell transplantation in a humanized mouse model. Notably, the stem cells were relatively resistant to the mAb treatment and their hematopoietic activity recovered quickly.…”

Donor-targeted serotherapy as a rescue therapy for steroid-resistant acute GVHD after HLA-mismatched kidney transplantation

“…Additionally, a positive donor cell/recipient serum crossmatch is associated with the protective effect against GVHD after intestinal/multivisceral transplantation . In 2014, Nakauchi's group reported the use of donor‐specific anti‐HLA A2 monoclonal antibodies to prevent the occurrence of GVHD following the transfer of human HLA A2+ peripheral blood mononuclear cells into NSG mice …”