Purpose: Tofacitinib is a Janus Kinase Inhibitor currently approved by FDA for treatment of rheumatoid arthritis. In considering its effect in reducing B cell proliferation and autoimmune antibodies, we recently carried out study to evaluate whether tofacitinib has suppressive effect on alloantibody responses in a skin graft model of HLA-A2 sensitization.

Methods: For de novo alloantibody suppression, naïve C57B/6 mice were sensitized with skin graft (SG) from a HLA-A2 expressing transgenic mouse and randomly divided them into two groups. In the treatment group, SG recipients received toficitinib (CP690550) by IP injection at a dosage of 50mg/kg/day for 14 days. Control mice received IP injections of polyethylene glycol 300 (Solvent for tofacitinib). For recall DSA suppression studies, mice were re-immunized with a second SG from a HLA-A2 mouse at Day 90 post-first skin grafting, and received tofacinitib treatment or control as described above. Blood samples were collected weekly. Donor-specific antibodies (DSA) were measured in a flow-cytometric antibody binding assay.

Results:

Tofacitinib significantly suppressed de novo DSA IgM at day 14 (10.01±5.58 MFI vs control: 16.88±4.5, p<0.05). DSA IgG antibodies were significantly reduced at Day 14 (63.43±6.65MFI vs. control 207.56±48.06, p<0.05) and Day 21 (tofacitinib: 333+78MFI vs. control: 407+18MFI). However, tofacitinib treatment did not have suppressive effect on recall DSA IgG antibody responses following re-sensitization.

Conclusion: Our data suggest: 1). Toficitinib can supress de novo DSA, both IgM and IgG alloantibodies. 2). Tofacitinib alone, may not have the capacity to substantially reduce recall DSA antibodies. Based on the suppressive effect of tofacitinib on de novo antibody responses use of Janus Kinase Inhibitor in combination therapies with other anti-T, B/plasma cell regiment may have a strategic role in de-sensitization of highly HLA sensitized patients or for the prevention of de novo development of DSA post-transplant.

CITATION INFORMATION: Chai N.-N, Wu G, Kim I, Klein A, Jordan S. Effects of Tofacitinib (JAK-3 Inhibitor) on De Novo HLA-A2 Antibody Production in a Mouse Model of Allo-Sensitization. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress