Summary The role of natural killer (NK) T cells in the development of lupus‐like disease in mice is still controversial. We treated NZB/W mice with anti‐NK1.1 monoclonal antibodies (mAbs) and our results revealed that administration of either an irrelevant immunoglobulin G2a (IgG2a) mAb or an IgG2a anti‐NK1.1 mAb increased the production of anti‐dsDNA antibodies in young NZB/W mice. However, the continuous administration of an anti‐NK1.1 mAb protected aged NZB/W mice from glomerular injury, leading to prolonged survival and stabilization of the proteinuria. Conversely, the administration of the control IgG2a mAb led to an aggravation of the lupus‐like disease. Augmented titres of anti‐dsDNA in NZB/W mice, upon IgG2a administration, correlated with the production of BAFF/BLyS by dendritic, B and T cells. Treatment with an anti‐NK1.1 mAb reduced the levels of interleukin‐16, produced by T cells, in spleen cell culture supernatants from aged NZB/W. Adoptive transfer of NK T cells from aged to young NZB/W accelerated the production of anti‐dsDNA in recipient NZB/W mice, suggesting that NK T cells from aged NZB/W are endowed with a B‐cell helper activity. In vitro studies, using purified NK T cells from aged NZB/W, showed that these cells provided helper B‐cell activity for the production of anti‐dsDNA. We concluded that NK T cells are involved in the progression of lupus‐like disease in mature NZB/W mice and that immunoglobulin of the IgG2a isotype has an enhancing effect on antibody synthesis due to the induction of BAFF/BLyS, and therefore have a deleterious effect in the NZB/W mouse physiology.
Oral tolerance can be defined as the inability of an adult animal to produce specific antibodies or cellular immune responses upon conventional immunization, after oral antigenic administration. Recently, the oral administration of antigens has gained renewed interest because of the possibility of inducing tolerance in nonimmunized adult animals and, consequently, opening up the theoretical possibility of preventing or treating diseases caused by malfunction of the immune system. This strategy has been proven to be useful in the prevention of allergic and autoimmune diseases in rodents, as well as in the amelioration of certain autoimmune diseases in humans. Although there is experimental and clinical evidence for the usefulness of oral tolerance in medical practice, the mechanisms responsible for this phenomenon are still poorly understood, and the results obtained are not always satisfactory. Herein, we show that the thymus is required for the induction and maintenance of oral tolerance, providing evidence that it is not a pure form of clonal deletion-based peripheral tolerance. Oral tolerance could therefore depend on the formation and release to the periphery of regulatory T cells, such as gammadelta or alphabeta T cells, by the thymus. This finding may have profound implications for the treatment of autoimmune diseases, since most of them are associated with thymic hypofunction. On the other hand, due to so far unknown mechanisms, the intraperitoneal co-administration of normal IgG to mice orally treated with tolerogen leads to a sustained and intense immunological tolerance, both in euthymic and thymectomized mice, including those of the lupus erythematosus-prone NZB x NZW lineage. This approach for inducing and maintaining tolerance in thymus-deficient conditions is discussed and put forth herein as a new evidence-based proposition for the therapy of autoimmune diseases.
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