Journal of Antioxidant Activity

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Antioxidant Activity-Innate Immunity-Charles Mills

United States

BioMedical Consultants.

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Charles Mills


16930 197th St. N,
Marine, MN 55047,
United States.

Research Interests:

Innate Immunity, M1 and M2 Macrophages, Cancer, Atherosclerosis, Autoimmunity, Nitric Oxide, Arginase, Ornithine


  • Dr. Mills specialty is Innate Immunity and Cancer. 
  • In his PhD work at the University of Chicago, and as a post doc at the Trudeau Institute, he focused on identifying what type of T cell response a host makes to cancer, and how to stimulate it with Biological Response Modifiers (1, 2).  
  • He (like most in the 1970’s and 80’s) believed that cancers were "foreign".  But, evidence accumulated that most human cancers are not recognized by specific T cells.  
  • Therefore, as an Assistant Professor at Brown University, he came to focus on macrophages (Innate Immunity).  
  • These investigations lead to his discovery and naming 2 types of macrophages, M1 and M2.  
  • How this discovery came to be is described below.   
  • First, he investigated what macrophages  (macs) were doing in wounds.  
  • He did because the concentration of Arginine specifically and precipitously declines in wounds (3).  
  • It turns out that macs are responsible because they metabolize Arginine to Ornithine (a precursor of polyamines and collagen necessary for repair).  
  • During these investigations, it was discovered that macs could also metabolize Arginine to Nitric Oxide that is the main molecule they use to kill pathogens and anything else nearby (e.g., cancer cells, normal tissue) (4, 5).  
  • Thus, macs could express polar - opposite responses depending on the type of inflammation (reviewed in 6).  In particular, in wounds and in growing tumors, macs primarily made Ornithine (7).  
  • In contrast, during killing of pathogens or in a rejecting tumor, macs primarily made Nitric Oxide (7).  
  • The set of experiments that followed at the University of Minnesota was the reason he named these 2 types of macs, M1 and M2. 
  • He showed that macs from SCID mice (no T or B cells) making NO or Ornithine dominate responses, stimulated nave T cells to make a Th1 or Th2 response, respectively.  
  • These results indicated, therefore, that macs (Innate Immunity, M1/M2), not Th1/Th2 cells (Adaptive Immunity) were the cells that directed what type of immune response would occur (8).  
  • These findings have fundamentally changed our understanding of how immune responses work, and have stimulated new directions in immunotherapy against a myriad of diseases from cancer to atherosclerosis (reviewed in 9).