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It is known that blood from healthy individuals and patients suffering from various immunoinflammatory diseases contain autoantibodies (aAb) to certain cytokines and that patients treated with recombinant human cytokines may develop antibodies (Ab) reacting with the therapeutic protein and often also the native cytokine (1-8).

The immunological basis for induction of aAb to cytokines is not clear. In the case of therapy-induced cytokine Ab/aAb, the pharmaceutical formulation, route of administration, dosage and duration of therapy, and the immunological status of the patient all appear to be important (9).

The majority of cytokine aAb detected in humans are of the IgG type and found with highly different prevalences. The lack of standardisation in detecting cytokine aAb is a major concern because of the often insufficient characterisation of cytokine aAb provided in the literature.

The cytokine-induced Ab/aAb usually disappear after termination of therapy. In contrast, while transient appearance of naturally occurring aAb to some cytokines have been described, long lasting and stable levels is the rule in the case of Ab to interferon (IFN) alpha, IFN beta, interleukin-1 alpha (IL-1a), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (8).

The biological significance of the naturally occurring aAb is poorly understood. Animal studies show that efficient cytokine neutralisation can be obtained by administering relatively high doses of monoclonal Ab (mAb) to cytokines, and high levels of therapy-induced Ab have been shown to abrogate the effect of the administered cytokine.

An in vivo agonistic rather than antagonistic effect has been observed in situations where in vitro neutralising mAb are present at low levels, particularly if the cytokine is bound in small complexes (10). Hence, accelerated clearance of a cytokine has been observed if the mediator form complexes with more than two IgG molecules (11).

The most extensively studied cytokine aAb are those that in normal individuals bind IFN alpha, IL-1a and IL-6. These IgG aAb are of polyclonal origin. They form large immune complexes by binding selectively and with high avidity to native forms of the cytokines, thereby neutralising their activities in vitro and, most likely, in vivo.

Why autoantibodies to cytokines?

It is unknown why and how aAb are induced to some cytokines and not to others in apparently healthy individuals. However, cytokine-reactive B-cells seem to occur frequently. As T-cell help is thought essential for the production of high-affinity IgG aAb, termination of T-cell tolerance is likely to be involved in the course of events leading to aAb induction.

One possibility is that activation of cross-reactive B- and T-cells is initiated if a native cytokine as a hapten binds to a carrier encoded by microorganisms (8). For example, poxviruses and herpesviruses encode IFN receptors, as well as TNF-, IL-1- and IL-6 receptors (12). Many of these are truncated and lack the transmembrane domains; the receptors are therefore secreted from the infected cells. Some resemble their host counterparts, whereas others have functional similarity but little homology, favouring their role as immunological carriers. A chronic or repeated infection, or a permanent break in T-cell tolerance to epitopes on the native cytokine would explain a continued production of these aAb.

Cited references:

1. Bendtzen K, Svenson M, Jønsson V, Hippe E. Autoantibodies to cytokines - friends or foes? Immunol Today 1990; 11:167-9.

2. Kazatchkine MD. Natural IgG autoantibodies in the sera of healthy individuals. J Interferon Res 1994; 14:165-8.

3. Bendtzen K, Hansen MB, Ross C, Svenson M. Cytokine autoantibodies. In: Peter JB, Shoenfeld Y, editors. Autoantibodies. Amsterdam: Elsevier Science B.V.; 1996. p. 209-16.

4. Hansen MB. Human cytokine autoantibodies. Characteristics, test procedures and possible physiological and clinical significance. APMIS 1996; 104, Suppl. 59:1-33.

5. Antonelli G. In vivo development of antibody to interferons: An update to 1996. J Interferon Cytokine Res 1997; 17, Suppl. 1:S39-S46.

6. Multiauthors. A review of interferon immunogenicity. Based on a roundtable workshop held in London, United Kingdom, 9 February 1996. J Interferon Cytokine Res 1997; 17, Suppl. 1:S1-55.

7. Special issue. Biotherapy 1997;10.

8. Bendtzen K, Hansen MB, Ross C, Svenson M. High-avidity autoantibodies to cytokines. Immunol Today 1998; 19:209-11.

9. Scharenberg JGM, Stam AGM, von Blomberg BME, Roest GJ, Palmer PA, Franks CR, Meijer CJLM, Scheper RJ. The development of anti-interleukin-2 (IL-2) antibodies in cancer patients treated with recombinant IL-2. Eur J Cancer 1994; 30A:1804-9.

10. Klein B, Brailly H. Cytokine-binding proteins: stimulating antagonists. Immunol Today 1995; 16:216-20.

11. Montero-Julian FA, Klein B, Gautherot E, Brailly H. Pharmacokinetic study of anti-interleukin-6 (IL-6) therapy with monoclonal antibodies: enhancement of IL-6 clearance by cocktails of anti-IL-6 antibodies. Blood 1995; 85:917-24.

12. Spriggs MK. One step ahead of the game: Viral immunomodulatory molecules. Annu Rev Immunol 1996; 14:101-30.