Reexamining the Nature of the Responding Unit

The major histocompatibility complex (MHC) in several species is highly polymorphic with several different alleles and many different antigens associated with each MHC. Studying the graft-versus-host (GVH) response in the chicken, in which lymphocytes respond to MHC differences, Simonsen noted that up to 3% of lymphocytes respond to a single difference in the MHC (1). A similar high frequency of responding units exists in the mixed leukocyte culture (MLC) test (2-4), a model of the recognition phase of the GVH reaction. In the MLC test, responding lymphocytes of one animal enlarge, exhibit enhanced incorporation of radioactive thymidine, and divide if they encounter MHC differences on allogeneic stimulating cells. With the very great number of different alleles (and therefore antigens) associated with the MHC, possibly compounded by the existence of still different antigens to be recognized which are associated with xenogeneic MHC's, it has been suggested that the very high frequency of initially responding units in MLC is not consistent with clonal selection theory-. Many different explanations have been offered to explain this apparent inconsistency. Most recently the suggestion has been made that the normal MLC response is directed only at allogeneic differences since xenogeneic responses in MLC were markedly lower than allogeneic ones using conventional (cv) animals (5) and further, germfree (gf) animals showed no xenogeneic response while responding normally in allogeneic mixtures (6). If the number of different allogeneic antigens which must be recognized is not too great, and only allogeneic antigens can cause MLC activation, these findings would help resolve the inconsistency. We have presented data which show that the xenogeneic and allogeneic responses in cv animals are in many cases comparable (7).