Environmental saprophytes the variable efficacy of BCG and the testing of new vaccines

It is important to emphasize that Figs 1—3 demonstrate that heightened susceptibility can be achieved by evoking a Th2 response to an organism that is only distantly related to M. tuberculosis, clearly indicating the crucial role of responses to 'common' antigens, probably including the stress proteins (Hernandez-Pando et al 1997). T cells that recognize these proteins constitute a major part of the T cell repertoire at birth (Fischer et al 1992). There is presumably a genetic component to the details of this repertoire. Subsequently, the pattern of response to these antigens, which have a crucial regulatory role (Cohen 1996), is 'educated' by exposure to environmental organisms. Again, there may be a genetic component because surveys of skin test responsiveness to the 'common' antigens revealed HLA associations (van Eden et al 1983).

Mycobacterial antigens are encountered by all humans as a result of contact with environmental mycobacteria, which are ubiquitous in soil and water supplies, but they are not part of the normal commensal flora, so the nature and extent of contact with them depends on where and how you live. Variable contact, priming protective Th1 responses (Fig. 2) or 'anti-protective' Th2 responses (Fig. 3) can explain the variable protective efficacy of Bacillus Calmette—Guerin (BCG). We suggest that in some environments where BCG fails, the recipients already have a Th2 component in their recognition of common antigens. If so, then the data in Fig. 3 suggest that a new vaccine, whether for therapeutic or even for prophylactic use, will need to be able to induce a Th2 to Th1 switch ifit is to do better than BCG. In order to test novel prophylactic vaccines in a more realistic way, the scheme outlined in Fig. 4 is suggested. The essence of this scheme is that animals should first be primed so that they have a Th2 response to selected components of M. tuberculosis, particularly to shared epitopes. Then the vaccine can be tested in a situation that mimics that seen in humans.

Immunological properties of an environmental saprophyte and systemic activation ofThl

Mycobacterium vaccae is the only environmental saprophyte to have undergone extensive immunological study, and it turns out to have such potent

FIG. 4. Suggested schemes for the realistic testing of candidate vaccines before they are tried in humans. If, as suggested in this chapter, pre-existing priming of a T helper 2 (Th2) component by common antigens in the environment is a factor that contributes to the failure of Bacillus Calmette—Guerin vaccination in some countries, candidate vaccines must prove that they can work in mice primed to mimic this situation. It may also be important to consider whether or not the vaccine contains the epitopes to which a Th2 response already exists. com, common antigens; SpSp, species-specific antigens.

FIG. 4. Suggested schemes for the realistic testing of candidate vaccines before they are tried in humans. If, as suggested in this chapter, pre-existing priming of a T helper 2 (Th2) component by common antigens in the environment is a factor that contributes to the failure of Bacillus Calmette—Guerin vaccination in some countries, candidate vaccines must prove that they can work in mice primed to mimic this situation. It may also be important to consider whether or not the vaccine contains the epitopes to which a Th2 response already exists. com, common antigens; SpSp, species-specific antigens.

immunological effects that the influence of these common organisms on efficacy of BCG (Fine 1995) and on tuberculosis (Figs 1—3) is not surprising. When multiple doses of the M. vaccae-derived preparation SRL172 were administered intradermally to 36 patients with late-stage melanoma (in the care of Angus Dalgleish, St. George's Hospital), 41% showed an increase in the peripheral blood of T cells that spontaneously secreted IL-2 in vitro. These were detected by flow cytometry (B. Baban, A. Maraveyas, G. A. W. Rook, M. Westby, J. M. Grange, P. Lydyard, J. L. Stanford & A. G. D. Dalgleish, unpublished work 1997) and reached 60—70% of all T cells in some patients. There was a correlation between the appearance of these cells and a good clinical outcome, although the study was not designed to test therapeutic efficacy. The point that is relevant to tuberculosis is that SRL172 can systemically activate Th1 responses and cause the patients to 'dose themselves' with IL-2. This striking release of IL-2 was not accompanied by toxicity, which is the usual constraint upon the use of this cytokine.

M. vaccae also acts as a potent Th1 adjuvant. Mice given a single subcutaneous injection of SRL172 develop powerful Th1 cell-mediated responses to the hsp65 of M. leprae in their lungs (C. Wang, R. Hernandez-Pando & G. Rook, unpublished work 1997). The Th1 adjuvanticity can also be demonstrated using recombinant forms of M. vaccae expressing foreign proteins (Abou-Zeid C et al 1997), or modified forms to which antigens have been conjugated by Schiff base formation (C. Wang & G. Rook, unpublished work 1997).

Systemic down-regulation of Th2 responses

Before treatment with SRL172, some of the cancer patients discussed above had numerous T cells that secreted IL-4 after stimulation with TPA and calcium ionophore. These cells are rarely present in the blood of normal individuals and they tended to disappear before the spontaneously IL-2-secreting cells increased. This suggested that SRL172 might down-regulate Th2, and this was confirmed experimentally. Balb/c mice were pre-immunized with ovalbumin so that they had high and rising levels of IgE. The IgE production in vivo and the potential for IL-5 release by spleen cells cultured with allergen were both shut off by two injections of SRL172 (Wang & Rook 1998). This was a systemic, non-specific effect on Th2 activity, which was not accompanied by induction of an allergen-specific Th1 response and did not require simultaneous injection of the allergen.

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