Alpha-Melanocyte–stimulating Hormone Is Critical to Corneal Graft Survival

Corneal endothelial cells are critical for maintaining the cornea's transparency, and they are gradually lost with aging and certain ocular conditions. The loss rate is even higher after corneal transplantation, leading to tissue edema, increased opacity, and, ultimately, graft failure.

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α-melanocyte–stimulating hormone (α-MSH), a neuropeptide found in normal aqueous humor, is in direct contact with corneal endothelial cells and regulates both innate and adaptive immune responses. Researchers at Mass Eye and Ear's Department of Ophthalmology have demonstrated, for the first time that, in addition to this immunomodulation, α-MSH has a direct protective effect on corneal endothelial cell survival after transplantation.

Reza Dana, MD, MSc, MPH, director of the Cornea Service, and colleagues Ula V. Jurkunas, MD, associate director of the Cornea Service, and Jia Yin, MD, PhD, director of the Cornea Fellowship Program, report their findings in The American Journal of Pathology.

Syngeneic Transplantation

The researchers began with a mouse model of syngeneic corneal transplantation, in which the donor and receiver are genetically identical twins. Syngeneic grafting involves no antigen-specific alloimmune response, so there should be nearly universal acceptance and survival of the donor cornea.

Donor corneas were derived either from wild-type C57BL/6 mice or C57BL/6 mice that lacked melanocortin receptor 1 (MC1R), the receptor for α-MSH. The latter group was designed Mc1re/e. The donor corneas were grafted onto wild-type C57BL/6 recipients.

Eight weeks after transplantation, 100% of grafts survived in the group of mice that received wild-type donor corneas. In those with Mc1re/e corneas, no graft survived beyond week 4.

Thus, MC1R function in graft endothelial cells is indispensable for graft function, probably because of the anti-apoptotic effects of α-MSH.

Allogeneic Transplantation

The researchers then grafted donor corneas derived from either Mc1re/e or wild-type C57BL/6 mice onto BALB/c mice. None of the Mc1re/e grafts survived beyond week 4, whereas 43% of wild-type grafts survived at week 8 (P=0.005).

α-MSH was administered to half the mice receiving Mc1re/e tissue to determine whether it could rescue those grafts. The treatment reduced loss of corneal endothelial cells and apoptosis, but opacity scores and survival rates were similar to control grafts receiving saline.

These results indicate the effect of α-MSH on host immunity can't compensate for the critical cytoprotective function of MC1R signaling on endothelial function in donor corneas.

α-MSH Suppression of Alloimmunity

One week after allogeneic corneal transplantation, the researchers evaluated the effect of α-MSH treatment on the initiation of host immune responses in ipsilateral draining lymph nodes.

Consistent with its immunomodulatory effect, α-MSH administration led to an increase in the function of regulatory T cells and a decrease in effector T-cell response. These changes occurred regardless of donor type (Mc1re/e or wild type).

Conclusion

There is an urgent need for cytoprotective approaches that will prevent the loss of corneal endothelial cells during tissue storage and after transplantation. This study lays the groundwork for new therapies by showing α-MSH has a pivotal protective effect on the corneal endothelium, and loss of MC1R function in grafted donor corneas significantly decreases long-term graft survival.

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