Propuesta de Alternativa de Solución para la Problemática Observada

Patients with HF, CFS and cancer had increased levels of IL-4- producing CD4 T cells (Fig. 9.1a). HF and CFS patients had normal levels of IFN-y and IL-2 compared to healthy people whereas the cancer patients showed a Thl->Th2 shift with slightly reduced levels of IFN-y and IL-2, and increased levels of IL-4. Only the CFS patients and some cancer patients had increased levels of Igs to HSPs (Fig. 9.1b). Therefore, the most prominent difference between these disorders and the healthy controls was their levels of IL-4.

During the course of this research, over thirty healthy individuals were investigated, and none showed IL-4 production raised over 4.5 % of CD4 T cells. Another finding is that not all patients had raised IL-4. The patients with elevated levels of IL-4 were not tested several times p rio r to immunotherapy, so it is not known if their increased Th2 responses were transient or relatively permanent. If the IL-4 production occurs occasionally, it might be easily missed in some patients.

HF and CFS patients had elevated Th2 cytokine patterns without a diminished T h l response, unlike patients with mycobacterioses and cancer in whom both conditions exist. It seems likely that the immunopathological effects of raised levels of IL-4 are modulated by other factors including cytokines such as IFN-y and IL-2. Therefore, the T hl-T h2 balance is likely to be regulated differently in different disorders such as HF, CFS, cancer and mycobacterioses. The balance of these cytokines could account for the differences in pathology, symptoms, severity and prognoses of these disorders (DelPrete,1998).

Fig. 9.1a Cytokines in different immune disorders compared to healthy people

5 0 n 4 0 -J 3 0 - 2 0- 1 0- T H vs. Ca p<0.007

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Fig. 9.1b Anti-HSP IgG in different immune disorders compared to healthy people I I H ealthy (n = 3 0 ) □ HF (n = 4 0 ) DU C F S ( n = 1 2 ) 100 n 7 5 - Û O Ü ^ 50^ > 2 5 - H vs. CFS p<0.01 Cancer (n=20) H vs. CFS p<0.02

I

Figure 9.1a) The levels of IL-4 was raised in all the disorders (hay fever, chronic fatigue syndrome and cancer). Cancer patients also had lower levels of IFN-gamma and IL-2

Figure 9.1b) The levels of anti-HSP IgG were raised in only CFS but not in HF and cancer. However, two cancer patients (one with rectal cancer and the other with with lung cancer) showed raised IgG to HSPs, particularly HSP-70.

The p values in the figures were derived from the Mann-Whitney test. H= healthy HF= hay fever CFS=chronic fatigue syndrome Ca=cancer

In allergic disorders, Th2 cytokines are known to promote IgE production by plasma cells and the expression of IgE FcR by basophils and mast cells (Maggi, 1998). Interactions between IgE and FcR on basophils and mast cells are involved in the degranulation of inflammatory mediators such as histamine, prostaglandins and leukotrienes. These mediators are responsible for clinical symptoms of HF such as nasal congestion, pruritis, sneezing and increased mucous secretions.

In cancers, Th2 response may suppress T hl mediated immune activation of macrophages, natural killer (NK cells) and lymphokine activated killer (LAK) cells. This means that tumour infiltrating lymphocytes (TIL), NK cells and LAK cells are unable to lyse tumour cells and macrophages are unable to scavenge cellular debris. The immune system in cancer shows phenomena of tolerance or dormancy associated with Th2 response whereas the T h l response is known to favour the rejection of tumours.

In addition to the generalised symptoms attributed to cytokines such as fever and anorexia, patients with many disorders suffer from fatigue, malaise and depression. These neuropsychiatrie syndromes that co-occur with the host response to infection, inflammation and malignancies could be mediated by different cytokines (Hickie and Lloyd, 1995). It is not known whether the changes in different immune parameters are directly responsible for the cause of their disorders or whether they arise indirectly as a result of stress to the immune system. For example, the hypothalamus-pituitary-adrenal (HPA) axis involved in the regulation of physiological stress can be affected by cytokines such as lL-1 and lL-6.

Apart from pathogenic mycobacteria, other parasites and environmental factors could be responsible for inducing unfavourable immune response. Exposure to industrial pollutants and organopbospbates (in pesticides) can adversely affect the immune system. Some people are also known to develop unfavourable immunity following natural infections as well as vaccinations against infectious diseases. Such effects might result from a combination of factors such as genetic predisposition, vaccine preparations themselves, and environmental factors which modulate their responses.

The incidence of CFS has been unusually high in the veterans of the Gulf war who were known to have received cocktails of vaccines to protect them against poisonous gases and germ warfare (Rook and Zumla, 1997). Mixtures of high doses of microbial antigens could have induced Tb2 responses in these vaccinees. CFS patients have been found to have CD4 T cells with reduced IFN-y but normal IL-4 production compared to healthy people (Visser, 1998). Another study has found the LPS- stimulated production of IL-l-(3, IL-6 and T N F-a have been found to be increased in CFS compared to healthy people (Chao et al, 1991).

SSPF shows evidence of progressive inflammation of the central nervous system (CNS) leading to the loss of higher intellectual functioning and spontaneous myoclonic movements. The measles virus acquired after natural infection or vaccination has been linked with SSPF. Von Pirquet observed nearly a century ago, that measles infection led to the suppression of DTH in tuberculosis patients (von Pirquet,

cytomegalovirus, hepatitis B and HIV are also known to suppress DTH reactions to skin-test antigens. The loss of responses to common mycobacterial antigens is likely to be related to these phenomena. Lowered T h l response in the brain, possibly resulting from decreased XL-12 produced by measles infected macrophages is thought to facilitate the viral replication in the brain (Karp et al, 1996). The patient described in this study showed slightly raised IL-4, a low level of IL-2 but a normal level of IFN-y.

SEASONAL CHANGES OF CYTOKINES IN HAY FEVER (UF)

All the HF patients included in this study had seasonal disease which exacerbates during the pollen season or the summer period. HF patients were monitored in March, May, June and July; therefore the patients receiving placebo injections served as a suitable control group to study the seasonal effect on cytokines. Their immune parameters were found to change during this period. Although variations in experimental conditions between different months can not be totally ruled out, the changes found in the cytokine patterns are described below.

The cytokine profile of hay fever patients showed a T h l to Th2 shift from March to July with the reduction of T hl response and the increase of Th2 response. This is in agreement with findings reported by other investigators (Ohashi et al, 1997). Compared to the starting levels in March, IL-4 production by CD4 T cells increased in July (Fig. 9.2a) whereas their levels of IFN-y and IL-2 decreased (Figs. 9.2b-c). The levels of IL-2 and IL-4 appeared to have a reciprocal relationship with each other (Fig. 9.2a-b), for example IL-2 declined in May and July but increased in June. Inhibition of IFN-y and IL-2 after June might have resulted from the increased Th2 response seen during this period.

Fig. 9.2a Level of IL-4 (±SEM) of HF patients receiving placebo only

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Fig. 9.2b Level of IL-2 (±SEM) Fig. 9.2c Level of IFN-gamma (mean±SEM)

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Figures 9.2a-c) The placebo group represented the levels of IL-4, IL-2 and IFN-gamma production in March, May, June and July.

The main differences were seen between the levels of cytokines in March and July. The % of CD4 T cells producing IL-4 was significantly increased (p< 0.02 , paired t-test).

IL-2 production decreased significantly (p< 0.0007 , paired t-test).

IFN-gamma production was significantly reduced (p< 0.05 , paired t-test).

The same healthy controls were only tested in March and May; and they did not show significant differences in their cytolane levels. The mean of individual changes in cytokine levels were 4% for IFN-gamma, 8% for IL-2 and 0.5% for EL-4.

Healthy controls tested in March and July were different people, and they did not show statistical differences in their levels of IL-2, IFN-gamma and EL-4.

XXX represent when the patients received immunotherapy or placebo (on three occasions two weeks apart in March)

The changes in the levels of cytokines might reflect the changes in levels of allergens in the environment or the homeostatic regulatory mechanisms in action. The intrinsic changes in the immune parameters could have followed the extrinsic challenge by the pollen antigens. Given that HF patients already have raised levels of IL-4 in March before the hay fever season, low doses of pollen antigens, other cross-reactive o r even unrelated antigens may be important in inducing or maintaining the Th2 response.

Another feature of cytokine production was the sequence in which different cytokine peaks appeared: the IFN-y peak was seen in May, IL-2 in June; followed by a prominent IL-4 peak in July. This might represent a physiological Th2 response to dampen the primary T h l response. Such periodic shifts might be regarded as a normal regulatory response. Production of appropriate cytokines in particular amounts, order and duration may be necessary for an adequate immune response. Problems could arise if a particular cytokine was produced in the wrong order or in an excessive amount, or if it cannot be reduced by feedback mechanisms.

The seasonal changes in cytokine levels of HF patients represent the snap-shots of many changes taking place. The changes in immune parameters described above only serve to emphasise the complicated networks involved in different immune pathways. It is important to consider the immune system as a collection of dynamic responses with homeostatic regulations constantly adapting to challenges. Furtherm ore, the situation in the peripheral blood only indirectly indicates what is happening at the site of pathology. Even chronic diseases that show relatively stable characteristics could be the result of many compensatory interactions.