Académie royale de Médecine de Belgique

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Erna Möller (Suède)

(Séance du 28 octobre 2000)

HOW ALLOANTIGENS ARE RECOGNIZED BY THE IMMUNE SYSTEM       

par Mme E. MÖLLER (Clinical Immunology – Karolinska Institute - Suède).

Rejection of organ transplants is conventionally believed to be caused by a cellular immune response specifically directed against HLA alloantigens present on grafted cells.  However, alloantigens cannot be recognised as such, since the specific T cell receptors recognise a complex of HLA antigens in association with peptides.  The specific T cell repertoire, i.e. the collection of T cell clones that are present in the secondary lymphoid organs of an individual, is formed as a result of selection processes in the thymus during T cell maturation, resulting in the selection processes in the thymus during T cell maturation, resulting in the selection of T cells equiped with receptors to recognise self HLA antigens, associated with self or foreign peptides.  As a consequence, the T cell clones of an individual are selected according to the individual’s own HLA phenotype.  Therefore, the specific interaction between specific T cell receptors and donor HLA alloantigen-peptide complexes would have to depend on cross-reactivity with self-HLA-peptide complexes.

It is well established the T cell clones selected to react against foreign peptides expressed by the individuals own (self) cells, can also cross-react against a selected set of allogeneic cells, providing support for the cross-reactivity model presented above.  Therefore, “specific” sensitisation against allogenic cells can take place in the absence of a specific allogenic stimulus.  Since specific T cell immunity, in a given host-donor combination, cannot be tested adequately in vitro, early graft rejection due to earlier cross-immunisation may occur.

HLA alloantigen-peptide complexes can activate host immunity provided the graft contains professional antigen-presenting cells, such a dendritic cells, an activation pathway referred to as “direct”.  However, alloantigens can also be released from cells in the graft and taken up by host antigen-presenting cells, as self-HLA associated alloantigenic peptides, a pathway of activation which is referred to as “indirect”.

It is generally assumed that both direct and indirect activation pathways contribute to the cellular immunity which may lead to graft rejection.  It is important to note that indirectly activated HLA class I restricted CD8+ cytotoxic T cells cannot exert a cytotoxic effect on target cells in the graft, unless complexes of self-HLA-allogenic peptides cross-react with allo-HLA-allogenic peptides expressed  by cells in the graft.  The infiltration on the graft by host inflammatory cells could, however, provide an efficient environment for CD4+ T cell-mediated delayed type hypersensitivity reactions, even following indirect activation of T cell allospecific immunity.

Humoral alloimmunity is directed against alloantigenic determinants expressed by the foreign HLA antigens as such.  Humoral alloimmunity is rarely demonstrated in the absence of specific alloimmunisation : therefore the presence of specific donor-reactive antibodies is usually a sign of specific alloimmunity.

Rejection of organ grafts can be caused either by a cellular immune response, by a humoral immune response or by a combination of both.  The efficient use of immunosuppressive drugs to prevent and treat graft rejection will depend on better knowledge of the mechanisms responsible for rejection in the individual patient case.

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