Antibody mediated rejection and donor specific antibodies are important causes of both early (hyperacute) and late (chronic) graft loss. Bruton tyrosine kinase (Btk) is required for B cell activation following binding of the B cell receptor (BCR). It also plays a crucial role in mast cell activation through the high-affinity IgE receptor. BTKB66 is a potent, orally-administered, selective, covalent inhibitor of Btk. We have previously shown that it can target neutrophils and macrophages and inhibit their activation. Given these properties, it holds great promise in modulating sensitization pre- and post-transplantation.

To examine the role of Btk, and by inference B-cell antigen receptor, activation in mouse skin transfer sensitization, orthotopic full-thickness skin grafts (0.5 cm in diameter) from wild-type BALB/c (B/c) donors were sutured bilaterally onto the flanks of C57BL/6 mice (B6) recipients. Graft survival was assessed daily by visual inspection. Skin allografts and draining lymph nodes were harvested at defined time points and tissue RNA was isolated for gene expression analysis. Retro-orbital blood was taken at several time points for the measurement of donor specific immunoglobulin. 8 week old B6 mice were divided into three groups (n=5-6): 1) control (no skin transplantation), 2) treatment with oral vehicle alone; 3) treatment with oral BTK66 treatment. BTKB66 treated B6 mice generated a significantly lower amount of BALB/c specific IgG at weeks 2, 3, and 4 (Figure 1). Treatment with BTKB66 also prolonged skin graft survival when administered orally until rejection (Figure 2). Therefore, BTKB66 both inhibits the generation of donor specific antibodies and prolongs allograft survival in mice.

CITATION INFORMATION: Datta N, Palumbo T, Kupiec-Weglinski J, Zarrinpar A. Inhibition of Bruton Tyrosine Kinase Blocks Sensitization in Response to Allogeneic Skin Transplantation and Prolong Skin Graft Survival. Am J Transplant. 2017;17 (suppl 3).

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