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The immune parameters seen in these patients are likely to have resulted from complex interactions between the hosts and parasites and prolonged chemotherapy. These patients had mycobacterial diseases caused by five different species, and had five co-existing immune disorders. Mycobacterial species responsible for diseases included

M.tuberculosis, M.avium-intracellulare, M.xenopi and M.chelonae

which have been described previously in chapter 1 (section 1.1.3.1).

Very little is known about the roles of cytokines in opportunist mycobacterioses. Tada et at (1995) have reported PHA induced IFN-y to be lower in patients with opportunist mycobacterioses compared to healthy controls. Although opportunist mycobacteria have a lower pathogenicity than M.tuberculosis, the significance of actual species responsible for opportunist mycobacterioses in unclear with regards to their immunopathology and their treatment using immunotherapy.

There is evidence that different mycobacterial species can cause a variety of pathologies. There are some examples of species-specific features of opportunist mycobacterial diseases such as M. avium

complex disease being progressive, and disease by M. kansasii being more insidious and chronic (Grange, 1996). However, there is no evidence that such differences are manifested in the hosts’ cytokine patterns. For example, one out of four M.avium-intracellulare patients had increased IL-4, while one out of two M .xenopi patients had raised IL-4 (TABLE 8.2).

TABLE 8.2 IMMUNE PARAMETERS OF PATIENTS BEFORE IMMUNOTHERAPY COMPARED WITH HEALTHY CONTROLS

subject Mycoba­ Other % C D 4 HSP-70-

cterium disorders IFN lL-2 lL-4 IsG ro .D .i

CK MDR-TB none 13 25 2.5 83

T

JB MDR-TB HIV 4 .6 i 3.0 i

6.1 T

12

BM MAIC none 6.9 i

11

I

2.5 54

JBA MAIC none

11

16 4.1 71

T

JH MAIC W G 7.0 i

10

i 6.7

T

82

T

MM MAIC CF 6.3 i 9.8 i

1.0

37 JR chelonae CF 6.5 I 7.4 i

2.0

39 SM x e n o p i Asthma 38

Î

22

9.5

T

82

T

MG x e n o p i Asthma 9 15 0.9 78

T

MP szulgai none 15 23 3.6 51 HEALTHY (mean, n=30) none none 17± 4.9 29± 9.1 2.9 ±

0.8

27+ 17

MAIC= M.avium-intracellulare complex WG= W egener’s granulomatosis

CF= Cystic fibrosis

Î = increased above healthy mean + 2 S.D.

i = decreased below healthy mean - 2. S.D.

Immune disorders found in patients with opportunist mycobacterioses included: HIV, asthma, cystic fibrosis and W egener’s granulomatosis. These disorders have been described previsouly in chapter 1 (section 1.1.3.2). Their effects on the immune parameters can not be deduced because of the small number of patients. Immunodeficient conditions associated with opportunist mycobacterioses are likely to be important determinants of pathogenesis and prognosis. When the host immune system is stressed, the whole host-parasite balance of power changes.

resulting in disease. Thus, mycobacteria which are normally non- pathogenic can cause damage to their hosts.

Opportunist mycobacterioses are commonly associated with immunodeficient conditions such as HIV. HIV, like mycobacterioses itself is reported to have an elevated Th2 response (Romagnani and Maggi, 1994). Altered cytokines are believed to increase susceptibility to mycobacterial diseases as well as accelerate progression to AIDS (Wallis and Ellner, 1994). JB, the patient with HIV and MDR-TB showed elevated levels of IL-4. This patient is believed to have acquired his MDR-TB from another patient, although this has not been proved by DNA fingerprinting.

The use of oral corticosteroids not only lowers the immunity against mycobacteria but it is also known to promote a Th2 cytokine response. These two effects might even be related as the Th2 response is known to exacerbate the immune dysfunction associated with mycobacterioses. The two asthmatics from this study had been on oral corticosteroid fo r over ten years before they developed mycobacterial diseases. The patient (JH) with W egener’s granulomatosis was also taking oral corticosteroids. The oral corticosteroids could have been responsible for increased IL-4 production in one of the asthmatics (SM) and the patient with Wegener’s granulomatosis (JH).

In the case of the two cystic fibrotics some immune parameters were similar. Both patients were much younger than other patients and healthy controls, and showed reduced T hl cytokines and low levels of IgG to HSPs. One of the two CF patients from this study, had been treated for allergic broncho-pulmonary aspergillosis (ABPA) with corticosteroids, a year before starting her immunotherapy.

Opportunist mycobacterioses are more common in the elderly population which is probably due to their lowered immune status and the progressive amount of lung tissue damage they have sustained. Also, it is possible that a long incubation period of decades may be required before the opportunist mycobacterioses can become established, possibly as a result of low dose tolerance. The mean age (±SD) of the eight patients (ie excluding the cystic fibrotics) was 49±15 years. Six of these eight patients were female. No age or sex related specific cytokine pattern could be detected among the healthy controls whose ages varied from 19 to 58 years.

There appeared to be a spectrum of T hl/T h2 cytokine responses in patients with opportunist mycobacterioses from this study. They could be divided into three groups: 1) reduced T h l response as well as elevated Th2 response 2) reduced T hl response only, and 3) normal cytokines similar to healthy controls.

REDUCED T H l AND ELEVATED TH2 RESPONSES

Of the ten patients with drug-resistant mycobacterioses, three (JB, JH, SM) had increased proportions of IL-4-producing CD4 T cells. These three patients did not show increased disease severity and symptoms compared to patients with normal levels of IL-4 although they all had co-existing immune disorders. JB and JH had reduced IFN-y and IL-2; whereas SM actually had high IFN-y production. JH and SM also had raised levels of IgG to HSP-65 and HSP-70. JB showed very low levels of anti-HSP Igs although HIV+ve TB patients in chapter 7 were found to have higher levels of anti-HSP Igs than HIV-ve TB patients. This shows an elevated Th2 response is not always associated with high level of IgG to HSPs.

REDUCED T H l RESPONSE ONLY

Three patients (BM,MM,JR) had reduced T h l and normal Th2 responses. All three patients had low levels of anti-HSP IgG. BM had no co-existing immune disorder whereas the other two patients had CF. It was surprising to find the CF patients with low levels of anti-HSP Igs because they harbour other parasites such as Pseudomonas aeruginosa in their lungs they would be exposed to high levels of microbial HSPs. It is possible that the HSPs of those microbes might not be cross-reactive with mycobacteria. The two CF patients were much younger (14 and 17 years) than the others whose mean age was above 50 years, which could account for some of the differences in their immune parameters.

NORMAL TH RESPONSE

The remaining four patients (CK,JBA,MC,MP) had relatively similar levels of IFN-y, IL-2 and IL-4 compared to healthy controls. Apart from one asthmatic on corticosteroids (MC), the other patients did not have co-existing immune disorders. Three of them (CK, JBA,MC), also had high levels of IgG to HSPs. Although, CK had similar cytokine levels as healthy controls, she had shown low T h l and high Th2 responses four months prior to immunotherapy. She had also received IFN-y therapy during this period which could have increased her T hl response and reduced her Th2 response. In spite of her cytokines returning to normal levels, she remained culture +ve for MDR-TB bacilli. This suggests that the Th2 to T h l shift was not sufficient fo r controlling MDR-TB in this patient.

ELEVATION OF ANTI-HSP IgG

Five patients showed elevated levels of anti-HSP IgG. These included three patients with normal levels of cytokines (CK,JB,MC) and two patients with increased IL-4 (JH,SM).

In document Microcréditos en los paises en vias de desarrollo (página 31-37)