Project 1: In Utero Chemical Exposures, Immune Status, and Childhood Leukemia

The Immune Development Project (Project 1) is led by Dr. Catherine Metayer and Dr. Xiaomei Ma, experts in the etiology of childhood leukemia.  Dr. Metayer is the Principal Investigator of the California Childhood Leukemia Study and Dr. Ma is one of two Principal Investigators of the California Mother-Child Birth Cohort.  These two investigators were instrumental in establishing these study cohorts, which provide the infrastructure for CIRCLE in the form of the biospecimens, interview data, and birth certificate data to be used in CIRCLE analyses.

We incline on our evidence to the belief that the solution of the problem of leukaemia lies rather in some peculiar reaction to infection than in the existence of some specific infective agent.


-J Poynton, H Thursfield and D Paterson, Great Ormond Street Hospital for Sick Children, London, 1922.

The Immune System and Childhood Leukemia

Leukemia is a malignancy of immune cells, called leukocytes, in the blood.  Inherently, the immune system and its development play a critical role in the initiation of childhood leukemia.  A rich literature shows that patterns of infection influence the risk of childhood leukemia. Exposure to more children for longer periods at an early age is protective against childhood ALL. It is surmised that exposure to a variety of infections educates and modulates the immune system, thereby lessening any leukemogenic-stimulating impact of new infections. Children lacking this early immune education will eventually be exposed to common childhood infections, but their uneducated immune systems are more likely to react aberrantly. This scenario is very similar to the “hygiene hypothesis” proposed to account for the increasing incidence of allergic diseases during the same time period that childhood ALL has increased.  It is hypothesized that even earlier immune development — development that occurs before birth — can set the trajectory towards leukemia risk.

How CIRCLE Measures Immune Development

To assess immune status at birth, CIRCLE measures a panel of seven immunomodulatory cytokines — interleukins IL-4, IL-6, IL-10, IL-12, and IL-13, Tumor Growth Factor (TGF)-β, and interferon (IFN)-γ — in neonatal blood samples.   CIRCLE investigators have found that children who later developed childhood ALL were born with profoundly depressed levels of an immunosuppressive cytokine, IL-10, when compared to matched controls who did not develop leukemia in the California Childhood Leukemia Study. A critical cytokine produced by regulatory T- and B-cells prior to birth, IL-10 is a major modulatory factor in successful maternal-fetal coexistence during pregnancy and in self-limiting immune responses to infection after birth. All infectious episodes in a healthy person are followed by a strong IL-10 response to damper immune responses following clearance of infections. The observation of low IL-10 at birth is highly suggestive that neonatal immune status may play a role in the etiology of childhood ALL, especially when considering the contribution of infection to the disease etiology.

A profound deficiency of IL-10 at birth in children who develop ALL later in life.  More details available from Chang et al. (2011). Cancer Epidemiol Biomarkers Prev. 20(8):1736-40. doi: 10.1158/1055-9965.EPI-11-0162.

What are cytokines?

A cytokine is a small protein which is released by cells.  Once released, cytokines influence the behavior of other cells through receptors, a process which can be thought of as an intercellular interaction or as intercellular communcation.  The cytokines include interleukins, lymphokines and cell signal molecules, such as tumor necrosis factor and the interferons.  An important group of cytokines are those which modulate the balance between humoral and cell-based immune responses through the regulation of the maturation, growth, and responsiveness of particular immune cell populations.  It is this group of cytokines — the ones which trigger inflammation and respond to infections — that are the focus of CIRCLE’s Immune Development Project.