Validity of delayed-type hypersensitivity and graft-versus-host reaction in testing of immunomodulators

Assessment of cell-mediated immunity (CMI) is an integral part of preclinical studies of pharmaceuticals and xenobiotics. Even if several tests to determine CMI are available, their interpretation is fraught with uncertainty whether identical results can be expected for each of these particular tests after the challenge with different immunomodulatory substances. This dilemma has been addressed by investigating the changes in two basic tests of CMI in vivo, i.e. delayed-type hypersensitivity (DTH) to sheep red blood cells and regional graft-versus-host reaction (GVHR), after the challenge with several immunomodulators. Both immunosuppressive modifiers (monoclonal anti-Thy 1, 2 antibody, cyclophosphamide, dexamethasone, methotrexate) and immunostimulatory agents (lipopolysaccharide, double-stranded RNA, thymostimulin, adamantylamide dipeptide, Propionibacterium parvum, BCG), were used. Most of the immunosuppressive drugs stimulated DTH while inhibiting GVHR. Most of the immunostimulating substances suppressed DTH and failed to affect GVHR. The results of tests were time dependent. Regional GVHR and DTH cannot be used as mutually interchangeable in immunomodulatory testing, and different results of these tests after exposure to a given agent can be expected. Possible mechanisms of action which would explain these differences are suggested in the discussion.