Cell-mediated rejection is defined histologically by the presence of an interstitial cellular infiltrate associated with infiltration by mononuclear cells :
- of renal tubules (tubulointerstitial involvement)
and/or - of the intima of the vessels (vascular involvement)
The two forms are often combined.
Actors involved
Mechanism
Where?
In the transplanted organ.
When?
Generally during the first 3 months post-transplant: very exceptionally before the first 5 days, most often one month after the transplant.
How is this done?
Two effectors are mainly responsible for cellular rejection: CD8+ T cells (cytotoxic T cells) and NK cells.
Cytotoxic CD8+ T cells in cellular rejection
The recipient’s T cells are activated by dendritic cells via the [HLA molecule - peptide] or [HLA molecule - peptide] complexes that they present on their surface.
(see alloreactivity). Once activated, they leave the lymph node draining the transplanted organ via the efferent lymphatic vessel then take the thoracic duct to join the systemic blood circulation to exert their effector actions.
The recipient’s T cells are then searching, within the tissues, for the complex [HLA molecule - peptide] or [HLA molecule - peptide] responsible for their activation.
The complexes [HLA molecule - peptide] being expressed exclusively by the cells of the transplanted organ, the T cells of the recipient will then infiltrate into the graft and cause cell lysis by cytotoxicity (see T cell activation).
NK cells in cellular rejection
Donor cells very often expressHLA molecules different from those of the recipient which have "educated" the NK cells, and can therefore become their target.
The NK cell uses the same cytotoxic tools as the cytotoxic T cell to lyse the graft cells (see NK cell activation).
If the donor and recipient are “HLA identical”, can there be cellular rejection?
Yes.Even in the absence of incompatibility on the major histocompatibility antigens (HLA and ABO), the donor necessarily synthesises peptides which are absent in the recipient, due to inter-individual genetic diversity. These peptides then constitute minor histocompatibility antigens expressed specifically by the graft cells. They can be presented indifferently by the dendritic cells of the recipient or the donor (because they have the same HLA molecules) to the T cells of the recipient, and cause their activation.
In the periphery, the only cells expressing the [molecule H LA - peptide] complex are the graft cells.
Consequences
Cell-mediated rejection has moderate consequences on graft survival if it is quickly treated. On the other hand, it is considered a risk factor for the development of Donor Specific Antibody (DSA) , and the occurrence of humoral rejection. Preventive and uninterrupted administration of immunosuppressive treatment is the best strategy to avoid these rejections.
Treatment of cell-mediated rejection is based on bolus administration of corticosteroids. In the event of vascular damage, recurrent cellular rejection or rejection resistant to corticosteroids, treatment with anti-lymphocyte antibodies is administered.
What needs to be remembered
Cell-mediated rejection is the consequence of the activation of CD8+ T cells and NK cells towards the donor cells, against which these cells will exert their cytotoxic properties. Cellular rejection has moderate consequences on graft survival if it is quickly treated. On the other hand, it is considered a risk factor for the development of DSA and the occurrence of humoral rejection further compromising the graft.