Efalizumab modulates T cell function both in vivo and in vitro.
BACKGROUND
The anti-CD11a mAb efalizumab has been successfully used in patients with moderate to severe psoriasis. Although peripheral blood leukocytes ubiquitously express LFA-1 (CD11a/CD18), it is assumed that efalizumab exerts its effects primarily on T lymphocytes by blocking migration and by interfering with the immunological synapse.


OBJECTIVE
To test the latter assumption, we asked whether efalizumab interferes with T cell proliferation induced by qualitatively and quantitatively different stimuli.


METHODS
We exposed PBMC isolated either from healthy or psoriatic individuals to titrated doses of plate-bound anti-CD3, PHA or allogeneic PBMC. Furthermore we stimulated normal PMBC (i) in the presence of efalizumab and (ii) after preincubation and removal of efalizumab.


RESULTS
We found that PBMC of efalizumab-treated psoriatics responded perfectly to PHA but were hyporeactive towards allogeneic leukocytes and anti-CD3. Similarly, efalizumab added to cultures of normal PBMC led to impaired proliferation induced by allogeneic leukocytes and by suboptimal, but not optimal concentrations of anti-CD3. To understand the underlying mechanisms we exposed normal PBMC to efalizumab under various conditions and stimulated them thereafter via anti-CD3. Whereas addition of soluble efalizumab to the culture did not modify the reactivity of PBMC to plate-bound anti-CD3, crosslinking of CD11a with efalizumab plus anti-human IgG rendered T cells less reactive to a subsequent anti-CD3 stimulus.


CONCLUSIONS
These observations suggest that efalizumab treatment induces a state of T cell hyporesponsiveness and provide an explanation as to why efalizumab is effective in patients with stable psoriasis, but often fails to control disease flares. When maintained over a prolonged period of time the observed T cell hyporeactivity may conceivably put efalizumab recipients at an increased risk of biologically relevant immunosuppression.
Department of Dermatology, Medical University of Vienna, Austria.
Frieder
F
Koszik
Georg
G
Stary
Nicole
N
Selenko-Gebauer
Georg
G
Stingl
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D040881:CD11a Antigen / Q000276:immunology*; D016022:Case-Control Studies; D002464:Cell Migration Inhibition / Q000276:immunology; D049109:Cell Proliferation; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology; D007165:Immunosuppression Therapy; D066298:In Vitro Techniques; D007962:Leukocytes / Q000145:classification / Q000276:immunology; D007964:Leukocytosis / Q000209:etiology / Q000276:immunology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D011565:Psoriasis / Q000276:immunology* / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000502:physiology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D040881:CD11a Antigen; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; C472181:efalizumab