*Purpose: Despite the progress in immunosuppressive regimens, antibody-mediated rejection remains a major contributor to renal allograft loss in recipients with donor-specific antibodies (DSA). IRE1a, an endoplasmic reticulum (ER) stress sensor, is an activator of XBP1 which is required for plasma cell differentiation and antigen-specific antibody production. The goal of this study is to determine the role of B cell-specific IRE1a in renal allograft rejection under sensitized and non-sensitized settings.

*Methods: In non-sensitized groups, renal allografts from BALB/c mice were transplanted into bi-nephrectomy B cell-specific IRE1a KO (CD19^cre/+IRE1a^flox/flox) or their wild type (CD19^+/+IRE1a^flox/flox) littermates. Cells from spleens and renal allografts were used for phenotypical and functional analyses. In sensitized groups, KO and WT mice were challenged with C3H skin grafts and received C3H kidney allografts 2 weeks later; the recipients were either untreated or treated with FK506 (3mg/kg/day) from day-1 to day10.

*Results: Lack of IRE1a in B cells significantly decreased donor-specific antibody production in either sensitized or non-sensitized recipients post-transplantation. In non-sensitized recipients, the WT renal allografts developed severe rejection with a median survival of 49 days, whereas most KO allografts survived over 150 days (P<0.0001, vs control). Despite the comparable T cell infiltration seen in both WT and KO allografts at POD12, the long-term-survived KO allografts showed significantly diminished cellular infiltration, improved renal function, and intact renal structure than the WT allografts. The prolonged survival in KO allografts was associated with decreased frequency of plasma cells and increased frequency of CD5⁺CD1d^hi regulatory B cells, aligned with the augmented IL-10 production seen in KO B cells stimulated with LPS in vitro. Furthermore, in sensitized recipients, the WT allografts with a transient FK506 therapy were rapidly rejected in 13.5 days. In contrast, the majority of the KO allografts with the same FK506 treatment had a significantly prolonged survival to over 60 days (P<0.01, vs control).

*Conclusions: These results suggest that deficiency of IRE1a in B cells inhibited DSA production, promoted regulatory B cells, and protected renal allografts from rejection in sensitized and non-sensitized recipients, thereby offering a potential therapeutic target for antibody-mediated rejection.

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