Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case-control study

The study by Gilham et al. confirms the hypothesis that reduced
exposure to infection early in life has effects on the maturing immune
system that increase the risk of acute lymphoblastic leukaemia (ALL) and
possibly other malignancies. The immunological basis of this increased
risk is uncertain but it could be the result of the inadequate development
of immune surveillance mechanisms that detect cancer-specific antigenic
determinants. This suggestion raises the possibility of using vaccination
strategies to replace the environmental contacts that would otherwise lead
to immune maturation. Gilham et al. mention Haemophilus influenzae type b
vaccination in this respect but another possible vaccine is Bacille
Calmette Guerin (BCG) which, when given early in life, has been shown in
several studies to afford protection against ALL.1

In this context, a working group of the European Organization for
Research and Treatment of Cancer (EORTC) has shown that vaccination with
BCG early in life, as well as vaccinia vaccination and certain serious but
uncommon infections, reduces the risk of the subsequent development of
melanoma by around 50% and that, in comparison with those not vaccinated,
a history of one or other, or both, of these vaccinations is related to
significant improvement in the survival time of those developing
melanoma.2 Further investigations are required to confirm the protective
effect of BCG against leukaemia and melanoma and to determine whether it
protects against other cancers. If so, a re-introduction of this vaccine
could have significant impacts on human health.

Gilham et al. postulate that the inadequate priming of the immune
system due to a lack of exposure to infection permits subsequent
infections by unknown exogenous agents, probably viruses, to cause immune
dysregulation leading to ALL. This may occur but an alternative
possibility is that the causative agent is not an exogenous one but a
human endogenous retrovirus (HERV). In the case of melanoma, we have
suggested that a failure of immune surveillance permits expression of a
member of the HERV-K family of endogenous retroviruses.3 This expression
leads to intracellular changes resulting in malignant transformation and
also to the presentation of an epitope, HERV-K-MEL, on the cell surface.
Interestingly, BCG, vaccinia and the agents causing the protective
infectious diseases contain homologs of the HERV-K-MEL epitope and could
therefore afford protection by generating a population of cross-reacting
memory T cells that are involved in immune surveillance of pre-malignant
and malignant cells.

If such HERV-related epitopes are involved in ALL and other cancers
their identification could, perhaps, lead to the development of a vaccine
affording protection against a range of cancers.

John M.Grange

Centre for Infectious Diseases and International Health, University
College London. London, UK.

Bernd Krone

Klaus F. Kölmel

Departments of Virology and Dermatology, University of Göttingen,
Göttingen, Germany.

1. Grange JM, Stanford JL. BCG vaccination and cancer. Tubercle 1990;
71: 61-64.

2. Kölmel KF, Grange JM, Krone B, et al. Prior immunisation of patients
with malignant melanoma with vaccinia or BCG is associated with better
survival. An European Organization for Research and Treatment of Cancer
cohort study on 542 patients. European Journal of Cancer 2005, 41: 118-
125.

3. Krone B, Kölmel KF, Henz BM, Grange JM. Protection against melanoma by
vaccination with Bacille Calmette-Guérin (BCG) and/or vaccinia: an
epidemiology-based hypothesis on the nature of a melanoma risk factor and
its immunological control. European Journal of Cancer 2005, 41: 104-117.

Competing interests:
None declared