Chronic diseases in animals and immune checkpoint molecules

  In veterinary medicine, there are many chronic infections and cancers that give a huge impact on animal health; however, in some such diseases, no effective prophylaxis and treatment are available to date. Recently, T-cell exhaustion caused by immune checkpoint molecules, or immunoinhibitory molecules, is reported as one of the immune evasion mechanisms in chronic infections and cancers. In our laboratory, we are studying immune checkpoint molecules toward the development of novel preventive or therapeutic methods for chronic and intractable diseases in cattle, chickens, and dogs.

  An immune checkpoint molecule, programmed cell death 1 (PD-1), is a costimulatory receptor expressed on T cells and suppresses the effector functions when it binds to its ligand, PD-ligand 1 (PD-L1) or PD-L2. In chronic infections and cancers, PD-1 is expressed on antigen-specific T cells and aberrant PD-L1 expression is found on infected cells or tumor cells. Thus, suppression of T cells by the PD-1/PD-L1 pathway induces “exhausted” status in T cells, in which they cannot exert cytotoxic activity against the target cells. On the other hand, the suppression caused by the PD-1/PD-L1 axis is reversible, and the blockade of this pathway can restore effector functions of T cells. Therefore, PD-1/PD-L1 inhibitors, such as anti-PD-1 antibody, can be used as novel therapeutic agents against those intractable diseases.

 

 

   In our laboratory, we are analyzing the expressions of immune checkpoint molecules and their association with disease progression in various diseases in animals, including bovine leukemia virus infection, Johne’s disease, anaplasmosis, and mycoplasmosis in cattle, as well as Marek’s disease in chickens and malignant cancers in dogs. In addition, we have established monoclonal antibodies that can block the molecular interactions, to evaluate therapeutic potential of the blockade of immune checkpoint molecules in those diseases. Notably, in bovine leukemia virus infection, the provirus load in the infected cattle was significantly decreased by the treatment with therapeutic anti-PD-1 or anti-PD-L1 antibody, demonstrating that these antibodies could be novel biological drugs for the control of intractable diseases in cattle.