PATHOPHYSIOLOGY

The major antigenic differences between a donor and recipient that result in
rejection of transplants are differences in highly polymorphic HLA alleles. The
recipients T cells recognize donor antigens from the graft (the allogenic
antigens or alloantigens) by two pathways.
Direct Pathway
T cells of the transplant recipient recognize donor MHC molecules on
the surface of APCs in the graft. It is believed that dendritic cells carried in the
donor organs are the most important APCs for initiating the antigraft response,
because they not only express high levels of class I and class II MHC molecules
but also endowed with costimulatory molecules (e.g. B7-1 and B7-2).
The T cells of the host encounter the donor dendritic cells either within
the grafted organ or after the dendritic cells migrate to the draining lymph nodes.
CD8+ T cells recognize class I MHC molecules and differentiate into active
CTLs, which can kill the graft cells. CD4+ helper T cells recognize donor
class II MHC molecules and proliferate and differentiate into TH1 (and possibly
TH17) effector cells. Cytokines secreted by the activated CD4+ T cells trigger
a delayed hypersensitivity reaction in the graft, resulting in increased vascular

permeability and local accumulation of mononuclear cells (lymphocytes and

macrophages), and graft injury caused by the activated macrophages.
T cells are restricted to recognize foreign peptides displayed by self-MHC
molecules.
Why should these T cells recognize these foreign MHC? The probable
explanation is that allogenic MHC molecules, with their bound peptides,
resemble, or mimic, the self-MHC-foreign peptide complexes that are recognized
by self-MHC-restricted T cells.
Indirect Pathway
Recipient T lymphocytes recognize MHC antigens of the graft donor after
they are presented by the recipients own APCs. This process involves the
uptake and processing of MHC and other foreign molecules from the grafted
organ by host APCs. The peptide derived from the donor tissue are presented by
the hosts own MHC molecules, like any other foreign peptide. Thus, the indirect
pathway is similar to the physiologic processing and presentation of other foreign
antigens. The indirect pathway generates CD4+ T cells that enter the graft and
recognize graft antigens being displayed by host APCs that have also entered
the graft, and the result is delayed hypersensitivity type of reaction. However,
CD8+ CTLs that may be generated by the indirect pathway cannot directly
recognize or kill graft cells, because these CTLs recognize graft antigens
presented by the hosts APCs. Therefore, then T cells react to graft by the
indirect pathway, the principal mechanism of cellular rejection may be T-cell
cytokine production and delayed hypersensitivity.
It is postulated that the direct pathway is the major pathway in acute
cellular rejection, whereas the indirect pathway is more important in chronic
rejection. However, this separation is by no means absolute.