New insights into prevention of donor-specific corneal graft rejection

Allogeneic corneal grafts placed in "high-risk" human eyes have a very poor prognosis, and even intensive systemic immunosuppressive therapy is often of no avail. Because corneal transplants are the most common type of clinic al grafting performed in humans and because failure of corneal grafts in "h igh-risk" eyes is a prominent cause of blindness, understanding the immunol ogic bases of graft rejection and of developing donor-specific suppression are worthy goals for research. The development of rodent models to experime ntally explore orthotopic cornea transplants engendered significant new kno wledge during the 1990s. Due to the factors responsible for ocular immune p rivilege, it has been found that minor histocompatibility antigens, rather than antigens encoded within the major histocompatibility complex, are the most important initiators of alloimmunity after orthotopic corneal transpla nts, Minor histocompatibility antigens are presented to the recipient immun e system by antigen-presenting cells that migrate into the graft from the l imbus. Peptides derived from processing of minor histocompatibility antigen s are loaded onto "self" MHC molecules and presented to recipient T cells b y the so-called indirect pathway of allorecognition. It is now established that T lymphocytes (and cell-mediated immunity) rather than antibodies (and humoral immunity) are chiefly responsible for the destructive alloimmunity that follows orthotopic corneal grafting in rodents. Moreover, CD4(+) T ce lls of the T helper type 1 phenotype (rather than CD8(+) cytotoxic T cells) that effect delayed-type hypersensitivity are the more important proximate mediators of corneal graft rejection. Armed with this information, our lab oratory has developed novel strategies to prevent rejection of orthotopic c orneal transplants. Our hope is that we will discover donor-specific immuno suppressive therapy that will be useful in human beings.