Bacteriabacterial products as adjuvants

Selected microorganisms have been identified that can trigger particularly potent immunological responses. The immunostimulatory properties of these cells have generated interest in their potential application as adjuvants. Examples include various mycobacteria, Corynebacterium parvum, Corynebacterium granulosum and B. pertussis. Although some such microorganisms are used as antigens in vaccines, they are considered too toxic to be used solely in the role of adjuvant. Researchers have thus sought to identify the specific microbial biomolecules responsible for the observed immunostimulatory activity. It was hoped that these substances, when purified, might display lesser/no toxic side effects while retaining their immunostimulatory capacity.

Fractionation of mycobacteria resulted in the identification of two cellular immunostimulatory components, namely TDM and MDPs. Both are normally found in association with the mycobac-terial cell wall. TDM is composed of a molecule of trehalose (a disaccharide consisting of two molecules of a-d-glucose linked via an a 1-1 glycosidic bond), linked to two molecules of my-colic acid (a long-chain aliphatic hydrocarbon-based acid) found almost exclusively in association with mycobacteria. TDM, although retaining its adjuvanticity, is relatively non-toxic.

The structure of the native immunostimulatory MDPs was found to be N-acetyl muramyl-l-alanyl-d-isoglutamine. (N-Acetyl muramic acid is a base component of bacterial peptidoglycan.) Native TDM is a potent pyrogen and is too toxic for general use as an adjuvant. The molecular basis underlining MDP's adjuvanticity remains to be fully elucidated. Administration of MDP, however, is known to activate a number of cell types that play direct/indirect roles in immune function, and induces the secretion of various immunomodulatory cytokines (Table 13.14).

Table 13.14 Some cell types activated upon administration of MDP. Activation induces synthesis of a range of immunomodulatory cytokines by these (and other) cells

Cell types activated

Macrophages Mast cells

Polymorphonuclear leukocytes

Endothelial cells

Fibroblasts Platelets

IL-1

CSFs

Fibroblast activating factor B-cell growth factor Prostaglandins

Cytokines and other molecules induced

A number of derivatives were synthesized in the hope of identifying a modified form that retained its adjuvanticity but displayed lesser toxicity. Some such derivatives, most notably threonyl-MDP, muramyl tripeptide and murabutide, display some clinical promise in this regard.

Threonlyn-MDP, for example, has been included in the formulation known as Syntex adjuvant formulation-1 (SAF-1). Animal studies suggest that this adjuvant is non-toxic and elicits a good B- and T-cell response.

An additional bacterial component displaying appreciable adjuvanticity is the C. granulosum-derived p40 particulate fraction. p40 is composed of fragments of cell wall peptidoglycan and associated glycoproteins.

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