In summary, the current findings not only demonstrate the long-term in vivo efficacy of our new SMIs, but they also (i) provide further evidence that the CD40–CD40L PPI is susceptible to small-molecule inhibition and (ii) reinforce the potential for the induction of operational transplant immune tolerance and the prevention of T1D onset through the inhibition of this costimulatory ICP. The gene discussed is CD40; the disease is type 1 diabetes mellitus.