Peter Medawar studied skin grafts. If he took skin from animal A and put it on animal B it took, then fell off (was rejected) after 7 days. This was termed the first set response. If the experiment was repeated then the skin fell off in about half the time, this was termed the second set response.
He noted that the second set response was both systemic and donor specific. He also postulated the presence of at least seven proteins capable of provoking an immune response in rabbits. [Med44,Med45]