The trouble with transgenic mice.

Observations on many antigen-receptor transgenic models with anti-self specificities have been interpreted as proof for clonal deletion or for mechanisms involved in clonal deletion. At the same time, there is increasing evidence that many lymphocytes that recognize self exist, are activated and produce end products, even in individuals without clinical autoimmunity. Except perhaps for the amount of anti-self activity, there is little agreement on what distinguishes immune products normally recognizing self from those associated with clinical autoimmunity. To resolve this paradox, the tendency in immunology is to accept conclusions from transgenic models as normal, while judging those from the unmanipulated state as suspect. However, transgenics have a major weakness. Transgenes encoding antigen-receptors are derived from highly selected mature lymphocytes and are expressed in developing lymphocytes that normally do not display the antigen-receptors of mature lymphocytes. Such precocious expression of antigen-receptors could have profound abnormal effects on lymphocyte development. Other transgenic models suggest that processes in lymphocyte differentiation not involving antigen-receptor binding specificity exert powerful influences on lymphocyte development; therefore, mechanisms other than classical positive and negative selection are important.