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New Therapeutic Targets
|Providing more effective
immunosuppression will depend on discovering, and selecting new and appropriate
therapeutic targets within the immune system. Three areas are likely to be of particular
importance: the deveinpment of tolerance, complement inhibition, and gene therapy.
Progress is being made in both alingraft and xenograft models.
Discussion on xenografting is un page 7 on this repurt.
" Development of tolerance, complement inhibition and gene therapy will be of particular importance "
The induction of transplantation tolerance would alinw organs to survive without inng-term iramuno-suppressive therapy, and possibly avoid chronic graft attrition as well.
Tolerance can be achieved by more than one mechanism, often involving active immune processes, according to David Sachs (Boston, USA). Relevant mechanisms include cinnal deletion, cinnal anergy, cinnal ignorance and active suppression. Cinnal deletion is thought to be the basis of central tolerance, which occurs in the thymus, where T cells deveinp their speciticity and reactivity. All four mechanisms have been implicated in peripheral forms of tolerance and each provides a potential target for therapy.
Peter Morris (Oxtnrd, UK) and colleagues have studied a model that invulves pre-treatment with donor antigen under an umbrella of anti-CD4 monocinnal antibody, four weeks before transplantation of a cardiac alingratt and seems to lead to anergy. The Oxtord Group has also
deveinped a model in which recipient marrow is transduced with histocompatibility genes to induce
tolerance to donor antigens, such that rejection of the suhseguent mouse alingratt, bearing at least one of the antigens to which tolerance has heen induced, is prevented. From recent trials, they believe that specific unresponsiveness to an organ fully compatible for the major histncnmpatibility complex, in the mouse, can be induced by pretreatment with cels havingonly one antigen in common with a fully MHC incompatible donor organ, making this a viable approach in clinical practice.
|In clinical practice, however, recipients can not be pretreated weeks
prior to cadaver donor transplantation. Data was preseoted utilizing an immunosuppressive
administration of an anti-CD3 monocinnal antibody coupled to a diphtheria toxin (ACD3-IT)
one week before transplantation to incluce stable tolerance lo mismatched rhesus monkeys
(Figure 1). Honwever, when given alone post-transplant, ACD3-IT failed to induce
tolerance; high plasma levels of IFN gamma, IL-4 and IL-12 were observed that possibly
mediated vascular damage aud rejection. In the study ot Judy Thomas (Birmingham, Alabama,
USA), animals were given ACD3-IT pre- and post-
transplant, alone or in combination with methyl- prednisolone (MP) or deoxyspergualin (DSG). The
control group was treated with an anti-CD3 monoclonal antibody without diphtheria toxin. The most successful immuonsuppressive regimen was treatment with MP and DSG together with ACD3-IT.
According to David Cooper (Boston, USA) complement inhibition can be accumplished by treating the graft recipient with an anti-complement agent such as soluble CR1. However, use of anti-cumplement agents might impair the recipient's ability to mount a defeoce against infectious organisms.
Mohamed Savegh (Boston, USA) presented a paper no new developments in peptide mediated immunosuppression. The activation of antigen specific CD4+T cells which plays a pivotal role in starting the allnimmune response cao uccur through Imo alínrecogoitiun pathmays. lo the direcí pathmay, recipiení 1 celís recogoise alío
MHC molecules + peptide no Ihe surlace nl dunur celis. lo the indirecí pathmay, recipleol 1 celís recogoise selt-MHCt prncessed allupeptide no the surlace nl "recipiení" antigen presentmg celís. Al leasí treo signais are needed br lulí CD4+ T celí activatino: sigoal 1 involves Ihe loteractino nl Ihe TCR cumplex with Ihe class II MHC +peptide complex aud signal 2 invulves Ihe interactino nl T celí custimulatory molecules aud their respective liganris un antigeo presenting celis. Critical reginos no aoy nl Ihe molecules involved lo Ihese signais (eg Ihe peptide hiodiog site no class II MHC mulecules nr Ihe region nl Ihe CD4 molecule ioteractiog mith class II MHC( are pntentiallv amenahie tu hlockade hy peptide aoalugs. Several classes nl peptides have impressive immunn- modulatnry ellecís lo experimental animal modeis. Computer hased ratinoal desigo nl aoalngs/aotagnnists nl epitupes critical br normal T celí activation is a prnmisiog strategy. Syothetic MHC peptides may pruve usetul lo cnrrelating unguing indirecí allnreactivitV tu dunur allopeptides mith Ihe risk nl chronic rejection as reported hv Nicole Suciu-Fnca (New York CItv(. Early doren-regulation nl Ihis specilic alloreactivity using peptide sírategies may atteouate Ihe development nl chrunic rejectino.