MOLECULAR MARKERS OF CORNEAL IMMUNE PRIVILEGE: THE ROLE OF TSP-1, MIF, IL-1RA, IDO, AND FasL IN CORNEAL ALLOGRAFT REJECTION

DOI: 10.22138/2500-0918-2025-22-4-392-403 (In Russ)

A.A. Kuznetsov ¹, A.M. Bystrov ¹,², E.V. Davydova ¹,², Gavrilova T.V. ³, Chereshneva M.V. ⁴

¹ Chelyabinsk Regional Clinical Hospital, Chelyabinsk, Russian Federation;
² Federal State Budgetary Educational Institution of Higher Education «South-Ural State Medical University» of the Ministry of Healthcare of the Russian Federation,
Chelyabinsk, Russian Federation;
³ Federal State Budgetary Educational Institution of Higher Education «Perm State Medical University named after Academician E.A. Wagner» of the Ministry of Healthcare
of the Russian Federation, Perm, Russian Federation;
⁴ Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences,
Yekaterinburg, Russian Federation

Abstract. The cornea has a unique immune privilege provided by avascularity, absence of lymphatic vessels and active secretion of immunosuppressive factors (TGF-β, FasL, TSP-1). These mechanisms suppress inflammation and prevent the allograft rejection reaction. However, with injuries, infections, or chronic inflammation, protective barriers are disrupted.: neoangiogenesis is activated, infiltration by immune cells and dysregulation of the local cytokine balance occur. Mucosassociated lymphoid tissue (MALT) plays a special role in this process, which normally maintains tolerance, but when the cornea is damaged, it becomes a source of pro-inflammatory signals that trigger adaptive immunity against the transplant. The aim of the study was to analyze the dynamics of tear fluid biomarkers (TSP-1, MIF, IL-1Ra, IDO, FasL) to assess their role in the violation of the immune privilege of the cornea and the development of graft rejection. Materials and methods. The study included 55 patients who underwent end-to-end keratoplasty (2019-2024) with a «high risk» of graft rejection. Lacrimal fluid sampling was performed before surgery, 3, 6, 9, and 12 months after the intervention. Two subgroups were formed retrospectively: 1a – included patients with clinically and instrumentally documented transplant rejection at any time during the entire follow-up period (n = 40) and 1b (comparison) subgroup consisted of patients who did not have a rejection episode throughout the dynamic follow-up (n = 15). The control group for determining the reference values of the studied indicators in the lacrimal fluid consisted of persons without ophthalmological pathology (n = 22). The immunological study was performed by the enzyme immunoassay using test systems to determine the levels of the studied markers (Cloud-Clone Corp., China). The results were recorded on a Multiscan Plus tablet photometer (Labsystems, Finland) at the appropriate wavelength. Statistical processing was performed using the Mann-Whitney criterion (p<0.05). Results. In patients with corneal allograft rejection, an imbalance of markers was revealed: decreased TSP-1, overexpression of MIF; IL-1Ra deficiency; decreased levels of IDO and FasL. Discussion. The imbalance of the studied markers forms a vicious circle: a decrease in TSP-1 and FasL stimulates angiogenesis and inflammation, overexpression of MIF exacerbates chronic inflammation, and deficiency of IL-1Ra and IDO disrupts immune homeostasis. This leads to structural changes in the cornea (edema, vascularization, epithelial defects) and clinical signs of rejection. The data obtained emphasize that monitoring of these biomarkers in the lacrimal fluid makes it possible to detect early signs of loss of immune privilege, which is critically important for timely correction of therapy. Conclusion. The study confirms that molecular analysis of tear fluid makes it possible to identify early signs of loss of immune privilege. The findings highlight the importance of a comprehensive approach to monitoring corneal immune privilege markers for predicting rejection and optimizing clinical management of patients after keratoplasty.

Keywords: corneal transplantation, rejection, cytokines, immune privilege
There is no conflict of interest.
Contact details of the corresponding author:
Aleksey M. Bystrov
highvision@bk.ru
Recieved 17.04.2025
For citation: Kuznetsov А.А., Bystrov А.М., Davydova Е. V., Gavrilova T.V., Chereshneva M.V.
Molecular markers of corneal immune privilege: the role of TSP-1, MIF, IL-1RA, IDO and FasL in corneal allograft rejection [Online] Vestn. Ural. Med. Akad. Nauki. = Journal of Ural Medical Academic Science. 2025, Vol. 22, no. 4, pp. 392–403. DOI: 10.22138/2500-0918-2025-22-4-392-403 (In Russ)

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Authors
Andrey A. Kuznetsov
Chelyabinsk Regional Clinical Hospital
Ph.D. of Medical Sciences, Head of the Regional Ophthalmological Center
cheloptic@mail.ru
Chelyabinsk, Russian Federation

Aleksey M. Bystrov
Chelyabinsk Regional Clinical Hospital,
Federal State Budgetary Educational Institution of Higher Education «South-Ural State Medical University» of the Ministry of Healthcare of the Russian Federation
Researcher at Ophthalmology Department No. 1, Senior Laboratory Assistant at the Department of Medical Rehabilitation and Sports Medicine
highvision@bk.ru
Chelyabinsk, Russian Federation

Evgeniya V. Davydova
Chelyabinsk Regional Clinical Hospital,
Federal State Budgetary Educational Institution of Higher Education «South-Ural State Medical University» of the Ministry of Healthcare of the Russian Federation
Doctor of Medical Sciences, Associate Professor, Head of the Department of Early Medical Rehabilitation, Professor of the Department of Medical Rehabilitation and Sports Medicine, davidova-ev.med@yandex.ru
Chelyabinsk, Russian Federation

Tatyana V. Gavrilova
Federal State Budgetary Educational Institution of Higher Education «Perm State Medical University named after Academician E.A. Wagner» of the Ministry of Healthcare of the Russian Federation
Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Ophthalmology
gavrilova.tv@mail.ru
Perm, Russian Federation

Margarita V. Chereshneva
Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences
Doctor of Medical Sciences, Professor, Honored Scientist of the Russian Federation, Chief Researcher at the Laboratory of Immunophysiology and Immunopharmacology
mchereshneva@mail.ru
Yekaterinburg, Russian Federation