Appendix L. 
353 
allogeneic recipient might induce tolerance to a subsequent allograft 
by causing deletion or inhibition of alloreactive T cells. 
T Cell Recognition Of Alloantigens 
Recognition of foreign, or allogeneic, HLA antigens by the recipient 
immune system is the major limitation to the survival of solid organ 
greifts. The central role of HLA molecules in allograft rejection is due 
to their role as restriction elements for T cell recognition of donor 
antigens and the extensive polymorphism displayed by the HLA 
molecules, which elicit host immune responses. Although progress 
has been made in the short-term survival of transplants, chronic 
immunologic rejection remains an impediment to long-term survival. 
The primary cause of acute rejection of transplanted organs is so- 
called "direct" recognition of whole allogeneic HLA antigens by 
receptors on the surface of recipient T cells. The direct recognition 
pathway involves recognition by recipient T cells of donor HLA class 
I and class II molecules, resulting in the generation of cytotoxic and 
helper T lymphocytes which play a pivotal role in the rejection 
process. In contrast, chronic rejection of transplanted organs results 
from so-called "indirect recognition" of donor HLA peptides derived 
from the allogeneic HLA molecules shed by the donor tissue. These 
foreign HLA molecules are taken up and processed by recipient 
antigen presenting cells (APC), and peptide fragments of the 
allogeneic HLA molecules containing polymorphic amino acid 
residues are bound and presented by recipient’s (self) HLA 
molecules to recipient (self) T cells. Although direct and indirect 
recognition of alloantigen generally leads to adverse graft outcome, 
tolerance induction may occur following exposure of the recipient to 
donor alloantigens prior to transplantation. Since this strategy is 
based on the nature and dose of the antigen as well as the route of 
administration, understanding how to control the balance between 
activation and unresponsiveness mediated by the direct and/or 
indirect recognition of alloantigen is a an area of active research 
which could lead to development of new therapies to prolong graft 
survival. 
Indirect allorecognition has been implicated in recurrent rejection 
episodes in various transplantation models of cardiac, kidney and 
skin grafts. Determinants on donor HLA molecules can be divided 
into two main categories: (a) the domincint allodeterminants that are 
efficiently processed and presented to alloreactive T cells during 
allograft rejection; and (b) the cryptic allodeterminants that are 
potentially immunogenic but do not normally induce alloreactive 
responses, presumably due to incomplete processing and/or 
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