Liver transplant rejection features memory cell priming, spatially differentiated networks and novel drug targets.
Ningappa, M.; Ashokkumar, C.; Murali, D.; Rajasundaram, D.; Higgs, B. W.; McDonald, W.; Schmitt, L.; Zhang, L.; Chattopadhyay, A.; kane, m.; Murphy, P.; Soltys, K.; Mazariegos, G.; Gupta, S.; Kar, U.; Billiar, T.; Zeevi, A.; Xu, Q.; Reyes-Mugica, M.; Subramaniam, S.; Sindhi, R.
Show abstract
Acute T-cell-mediated transplant rejection, the earliest contributor to immunological graft failure responds variably to T-cell suppression. Early rejection can co-exist with donor-specific antibodies which also shorten graft survival, without affecting graft histology visibly. Here, during early liver transplant rejection, blood leukocytes manifest primed T-cells with heat shock protein (HSP) signaling and transcriptional programs for memory cell expansion. Corresponding biopsies demonstrate upregulated immune synapse and proteasomal genes in T-cell-infiltrated portal and central regions of the liver lobule. With donor-specific antibodies, the intervening intralobular region demonstrates a germinal-center-like allograft response with upregulated CD40, chemokine, T-follicular and complement signaling, which intensifies along the direction of sinusoidal blood flow from portal to central regions. Proteasomal and HSP90 inhibitors suppress donor-specific alloresponses of T- and B-cells in blood samples from patients with early rejection. The molecular injury spectrum of early rejection is complex, spatially differentiated and reveals novel early immunosuppressive strategies to extend graft survival.
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