DEPLETION OF CD4(-THYROIDITIS() AND CD8(+) CELLS ELIMINATES IMMUNOLOGICAL MEMORY OF THYROIDITOGENICITY IN MURINE EXPERIMENTAL AUTOIMMUNE)

Experimental autoimmune thyroiditis (EAT) develops in genetically susc eptible mice after immunization with mouse thyroglobulin (MTg), and is mediated by T cells, both CD4(+) and CD8(+), infiltrating the thyroid . Previous work showed that depletion of CD4(+), but not CD8(+), cells with rat monoclonal antibodies (mAbs) interfered with EAT induction. To test if concomitant CD4(+) cell depletion and immunization led to E AT resistance, mice were reimmunized at an interval of 15 or 43 days a fter injection of CD4 mAbs. No resistance had been established; diseas e severity and anti-MTg titers were comparable to mice with primary im munization. Previous work also showed that treatment during advancing EAT with only CD4 mAbs on days 21, 25 led to long-lasting, reduced sev erity in EAT, whereas administration of CD8 mAbs alone reduced the sma ller CD8(+) subset only. However, therapy with both mAbs was most effi cacious; > 50% of thyroids were purged of all cellular infiltrate afte r only two doses. Moreover, T cells emerging subsequent to depletion w ere not retained in the thyroid, despite ongoing antibody production. To test if nondepleting CD4 and CD8 mAbs were similarly effective for therapy, mAbs of the IgG2a isotype were administered during advancing EAT. No effect on thyroidal infiltration was observed, indicating that modulation of the CD4 and CD8 antigen without depletion was insuffici ent for efficacious therapy. To determine if combined therapy with dep leting mAbs reestablished self tolerance, treated mice were reimmunize d on days 70, 77, when T cell recovery was nearly complete. Thyroiditi s was comparable to controls given primary immunization, despite high antibody levels. Thus, efficient depletion of both T cell subsets elim inated immunologic memory of thyroiditogenicity and represents a suita ble treatment modality for autoimmune disease.