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Novel compounds that inhibit the activation of CD4-positive T cells as immunosuppressive agents

Objective



The present proposal foresees the synthesis of peptides and, in the following, of peptidomimetics corresponding to a discrete, non-polymorphic domain of major histocompatibility complex (MHC) class II molecules. On the basis of theoretical considerations and preliminary results such compounds are expected to interfere with the antigen-specific activation of CD4-positive T cells through a novel mechanism of action. Thus, such peptides should not act through occupation of the antigen-binding groove of M:HC class II molecules nor through inhibition of the binding of CD4 coreceptors to MHC class II molecules.
Preliminary results have shown that linear, up to 16 amino acid long peptides corresponding to said domain, are indeed able to inhibit antigen-specific T cell activation as determined by measuring proliferative responses in mixed leukocyte reactions (MLR) and of T cell clones in response to their specific antigen. Further studies showed that the active peptides affected CD4-positive, but not CD8positive T cells. Reduced proliferation was paralleled by reduced production of interleukin 2 (IL-2), the main growth factor responsible for proliferation of activated T cells. On the other hand, no significant modification of the up-regulated expression of highaffinity IL-2 receptors was observed. These results are consistent with the hypothesized mechanism of action. More direct evidence in favour of this was obtained, on living cells, with a novel imaging technique.
The work programme foresees the synthesis of other peptides that will be shorter than the parent compounds and of constrained chemical structure. Further peptides and peptidomimetics will be synthesized having properties that should make them suitable for in vivo administration and, eventually, as pharmacological agents for diseases states that are the consequence of activation and expansion of CD4positive T cells. It is planned to perform, with these compounds, in vitro tests in order to quantify their immunosuppressive potency and to evaluate the functional consequences of their activity on T cells and, eventually, in vivo tests in animal models in order to evaluate their therapeutic potential.
In addition, we plan to implement the use of the indicated imaging technique. This shall expand our knowledge on the biological event that has suggested to us the possibility to synthesize molecules able to interfere with it. Compounds synthesized during the present project will be tested in this assay. Further activities that are expected to deepen our understanding of the functional consequences of said event foresee the generation of transfected cell lines expressing mutated forms of MHC class II molecules. Submission of the present proposal as well as the activities that led to its preparation are in fulfillment of a preparatory grant (Stage 1 Contract No. B104-CT97-9067) that has been awarded to two of the partners participating to the present network.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Centre National de la Recherche Scientifique
Address
Rue René Descartes
67084 Strasbourg
France

Participants (5)

Consiglio Nazionale delle Ricerche
Italy
Address

10043 Orbassano
IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
United Kingdom
Address
Ducane Road 150, Hammersmith Hospital
W12 ONN London
INBIOS Srl
Italy
Address
Via A. Olivetti 1
80078 Pozzuoli
UNIVERSITY OF ESSEX
United Kingdom
Address
Wivenhoe Park John Tabor Laboratories
CO4 3SQ Colchester
Università degli Studi di Napoli Federico II
Italy
Address
Via Mezzocannone 4
80134 Napoli