Vaccination strategies to reduce the risk of leukaemia and melanoma
Authors: J. M Grange, J. L Stanford, C. A Stanford, K. F Kolmel
Journal: Journal of the Royal Society of Medicine (2003)

In the industrialized world, the burden of infectious disease has been vastly reduced by improved standards of hygiene in the home and public places. But numerous studies, reviewed elsewhere,1-3 suggest that a price may be paid in the rising incidence of diseases such as asthma and autoimmune disorders. According to this hypothesis, the maturing immune system no longer encounters the many microbiological challenges that evolution has led it to ‘expect’, and which contribute to its maturation and pathways of regulation—in other words, to its ‘education’.

Some of the recent reviews of this ‘hygiene hypothesis’1,3 suggest that the postulates might be extended to other disorders with an immunological element, notably certain cancers. The ability of serious infections to induce regression of cancers has long been recognized. The phenomenon was observed in the 19th century in England, Germany and the USA by, respectively, Campbell De Morgan,4 Bruns5 and Coley.6 Coley induced erysipelas therapeutically in patients with sarcoma, with beneficial results in several cases. Since this was very risky in those pre-antibiotic days, he then experimented with extracts of streptococci and other bacteria and found these ‘Coley toxins’ to be likewise effective.

Not only may infections have an effect on established cancers but it is also possible that, by eliciting or enhancing antitumour immunity, they reduce the risk of tumours subsequently developing. In this context, Greaves observed that acute leukaemia, the commonest malignancy seen in children, occurs particularly in affluent societies.7 He therefore postulated that the disease is associated with an abnormal response to common infections of infancy and childhood associated with the altered environment of such societies. According to Greaves' hypothesis, the biological ‘norm’ is for the very young to encounter numerous infections, from the mother around the time of birth and from siblings and other contacts in infancy. Greaves therefore postulated that such infections would modulate the developing immune system, involving the expansion, suppression and elimination of certain T-cell subsets, in line with evolution, and that lifestyles in developed countries, with reduced exposure to such infections, would compromise this evolutionary adaptation of the immune system. The ‘immune proliferative stress’ resulting from an abnormal maturation of the immune system would favour mutations responsible for leukaemia. (It must be emphasized that Greaves' hypothesis refers to factors affecting the maturation of an intrinsically normal immune system. This is quite distinct from congenital or acquired immunosuppressive disorders which are associated with an increased risk of lymphomas rather than of leukaemia.)

Greaves' hypothesis has received strong support from studies in France and the USA.8,9 Both pointed to a relation between protection against acute lymphoblastic leukaemia and exposure to common infections as a result of daycare attendance, and demonstrated that the degree of such protection was related to the amount of time spent in daycare facilities. The French study also related protection to repeated early common infections, surgical procedures for ear, nose and throat infections and prolonged breastfeeding. The latter, according to Greaves, has multiple immunological effects on the infant and results in the oral transmission of bacteria and viruses that contribute to normal immune maturation.