Health Research Of Allied Forces
Project Summary

Title: The Role of Th1/Th2 Cytokine Balance in Gulf War-related Illness
Synopsis: This study using blood from humans measures cytokines (substances that coordinate the body's defense against illnesses) before and after antigens (like immunizations) to help determine whether or not multiple vaccinations against biological agents may change the immune system and lead to chronic fatigue.
Overall Project Objective: Examine the relationship between immunological markers of Th1/Th2 cytokine balance, biological warfare vaccines and Gulf War related illness.
Status/Results to Date: To date the investigators have: recruited GWVs with and without illness, as well as a group of control servicemen with similar symptoms who were either not deployed (Era controls) or deployed to the Bosnia conflict; completed the analysis of Th1 and Th2 cytokines, and obtained related data on vaccine administration. Evidence of Th2 skewing in symptomatic GWV (sGWV) was found. Levels of IL-4 secreting CD4 T cells in sGWV were higher compared with well GWV (wGWV; p<0.05) and symptomative Bosina/Era veterans (sBEV); p<0.05) in whom levels were similar. Levels of IL-10 producing CD4 cells were similar in sGWV and sBEV but were higher than in wGWV (p<0.005 and p<0.05, respectively). Levels of Th1 cytokine producing cells were similar in all groups. However, amongst Gulf War veterans, there was a significant trend for reduced levels of the Th1 cytokine IFN-g and non-significant trends for increased levels of the Th2 cytokines IL-4 and IL-10 with increasing numbers of vaccines administered. These data show that multi-symptom illness in Gulf War veterans is characterized by biased generation of cells secreting the prototypic Th2 cytokine, IL-4. Secretion of IL-10, a less specific Th2 marker, was associated with multi-symptom illness irrespective of deployment. Multiple vaccine exposure was associated with evidence of Th1/Th2 imbalance in favor of Th2, but since vaccine exposure in the symptomatic and well Gulf war veterans we studied was similar, we are unable to confirm a causative link between vaccines, Th1/Th2 balance, and illness.
Agency:Department Of Defense
Location:Guy's King's And St. Thomas' School of Medicine
P.I. Name:Mark Peakman, Ph. D.
Research Type:Clinical
Research Focus:Immune
Focus Category:Health Research Of Allied Forces
Study Start Date:January 31,2000
Estimated Completion Date:February 28,2002
Specific Aims: Investigate whether multiple vaccines, given under stress of deployment and with additional effects of a T helper 2 (Th2) adjuvant can skew the immune response towards a Th2 profile. The Th2 profile, characterized by cytokines interleukin-4 (IL-4) and IL-10, is associated with syndromes such as allergic disease, hypersensitivity and depression. It is based on the following hypothesized Th1/Th2 paradigm of immune regulation: The Th1/Th2 paradigm of immune regulation and its relationship to immune-mediated human disease is, briefly, that polarized Th1 cells secrete immune activating cytokines such as interferon-y, (IFN-y) and promote cell-mediated immune responses (eg killing intracellular parasites). Polarized Th2 cells secrete cytokines such as interleukin-4 (IL-4), IL-5 and IL-10. Th1 and Th2 cytokines have a tendency for mutual inhibition, potentially creating conditions under which subtle disturbances can lead to pathological imbalance over a period of time. An imbalance of Th2 over Th1 immunity is associated with allergic disease and hypersensitivity and mood changes including depression. These observations are hypothesized to create an imbalance in immune function that could be associated with Gulf War-related illness.
Methodology: Study whether self reported illness in GWVs is associated with a Th2 shift by examining Th2 (IL-4, IL-10) and Th1 (IL-2, interferon-y) intracellular cytokine staining in CD4 and CD8 T lymphocytes by flow cytometry after mitogenic stimulation. In addition, examine the generation of autoantibodies (representing a Th2 shift) in GWVs and appropriate control groups.
Most Recent Publications:

Skowera A, Sawicka E, Hotopf M, Varela-Calvino R, Unwin C, Hull L, Nikolaou V, Ismail K, Wessely S, Peakman M. Abnormal Th 1 Th 2 balance in Gulf War Illness. Lancet, Submitted. Article

Skowera A, Stewart E, Davis E, Cleare A, Hossain G, Unwin CE, Hull L, Ismail K, Wessely S, Peakman M. Antinuclear antibodies (ANA) in gulf war related illness and chronic fatigue syndrome (CFS) patients. Clin Exp Immunology, 129(2):354-8, Aug 2002. Abstract

Skowera A, Hotopf M, Sawicka E, Varela-Calvino R, Unwin C, Nikolaou V, Hull L, Ismail K, David A, Wessely S, Peakman M. T helper 2 type immune activation in Gulf War veterans with multi-symptom illness. N/A, Submitted for publication. Article