Timely blockade of ICAM-1.LFA-1 interaction prevents disease onset in a mouse model of emphysema

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From: Immunotherapy(Vol. 7, Issue 6)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 5,350 words
Lexile Measure: 1610L

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Author(s): Amy H Newton aff1 aff2 , Derek B Danahy aff1 aff3 , Marcia A Chan aff4 , Stephen H Benedict [*] aff1

Keywords:

autoimmune therapy; costimulatory blockade; emphysema; ICAM-1; selective immunotherapy; T cell

Emphysema, a form of chronic obstructive pulmonary disease (COPD), is characterized by progressive decline in respiration due to destruction of alveoli and narrowing of the airways [1 ]. Damage involves inflammatory mediators including proteases, cytokines, chemokines and reactive oxygen species. Emerging data from humans and mice suggest that the inflammation is a component of an autoimmune attack on lung tissue. Support for this is obtained by adoptive transfer of disease into naïve animals using T cells from mice with smoke-induced emphysema [ 2,3 ], and by observations that mice deficient in CD8+ T cells or MHC I fail to develop emphysema [2,4 ]. Additional support comes from observations of adaptive immune responses associated with emphysema [5-8 ] and the presence of oligoclonal T cells in emphysema patients [ 9,10 ]. Thus, it is likely that pathogenesis of emphysema involves T-cell driven attack on self proteins in an antigen-specific process reminiscent of autoimmunity and that therapeutic approaches that induce immune tolerance might be of utility.

Costimulatory blockade has been studied as an approach to induce antigen (Ag)-specific tolerance. In the context of autoimmune disease, a self protein, of which we are normally immunologically tolerant begins to be viewed as foreign by the immune response. This protein, processed normally to peptides and presented on HLA molecules, stimulates a comparatively small number of the 100 million T-cell Ag specificities available at any time in a human. These self Ags thus provide the stimulus to initiate an autoimmune attack that can also involve inflammation. A major goal in immune therapy is to inactivate only the T cells attacking self while allowing the remaining 100 million or so to continue to function. In the two-signal mechanism of T-cell activation [11-14 ], a first, Ag-specific signal, is delivered to the T cell by Ag peptide presented in the context of HLA/MHC. This signal activates the T cell and predisposes it to become anergic or enter apoptosis. The second signal is delivered when any of several cell surface proteins on the APC engages its counter receptor on the T cell. The second (fail safe) signal completes the activation process and rescues the T cell by preventing it from entering anergy or apoptosis. The best-studied costimulatory protein is CD28 but several other surface molecules also serve in this capacity, including the adhesion molecules (and counter receptors) LFA-1 and ICAM-1 [15-18 ]. Blockade of the second signal leaves signal 1 dominant and allows the T cell to die or go anergic. Antibody blockade of ICAM-1 and LFA-1 interactions in mouse models prevent autoimmune attacks [18,19 ] and facilitate organ transplants [20 ].

Previously, we observed that short peptides representing contact domains of ICAM-1 and LFA-1 [21 ] inhibited human T-cell function in a mixed lymphocyte in vitro model of bone marrow transplantation [22 ]. Recently, we demonstrated that the peptides...

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Gale Document Number: GALE|A422428337