Background. Allogeneic rejection is the most common cause of corneal graft
failure. The aim of this work was to establish the kinetics of cytokine and
chemokine mRNA expression before and after onset of corneal graft rejectio
n.
Methods. Intracorneal cytokine and chemokine mRNA levels were investigated
in the Brown Norway-->Lewis inbred rat model in which rejection onset is ob
served at 8/9 days after grafting in all animals. Nongrafted corneas and sy
ngeneic (Lewis-->Lewis) corneal transplants were used as controls. Donor an
d recipient cornea was examined by quantitative competitive reverse transcr
iption-polymerase chain reaction (RT-PCR) for hypoxyanthine phosphoribosylt
ransferase (HPRT), CD3, CD25, interleukin (IL)-1 beta, IL-1RA, IL-2, IL-6,
IL-10, interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), transform
ing growth factor (TGF)-beta1, and macrophage inflammatory protein (MIP)-II
and by nonquantitative RT-PCR for IL-4, IL-5, IL-12 p40, IL-13, TGF-beta2,
monocyte chemotactic protein-1 (MCP-1), MIP-1 alpha, MIP-1 beta, and RANTE
S (for regulated upon activation normal T cell expressed and secreted),
Results. A biphasic expression of cytokine and chemokine mRNA was found aft
er transplantation. During the early phase (days 3-9), there was an elevati
on of the majority of the cytokines examined, including IL-1 beta, IL-6, IL
-10, IL-12 p40, and MIP-II. There was no difference in cytokine expression
patterns between allogeneic or syngeneic recipients at this time. In syngen
eic recipients, cytokine levels reduced to pretransplant levels by day 13,
whereas levels of all cytokines rose after observed rejection onset in the
allografts, including TGF-beta1, TGF-beta2, and IL-1RA. The T cell-derived
cytokines IL-4, IL-13, and IFN-gamma were detected only during the rejectio
n phase in allogeneic recipients.
Conclusions. There is an early cytokine and chemokine response to the trans
plantation process, evident in syngeneic and allogeneic grafts, that probab
ly drives angiogenesis, leukocyte recruitment, and affects leukocyte functi
ons. After an immune response has been generated, allogeneic rejection resu
lts in the expression of Th1 cytokines (IL-2, IL-12 p40, IFN-gamma), Th2 cy
tokines (IL-4, IL-6, IL-10, and IL-13), and anti-inflammatory/Th3 cytokines
(TGF-beta1/2 and IL-1RA).