Reassessing the cryopreserved human amniotic membrane's low immunogenicity due to advances in histocompatibility

Human amniotic membrane (hAM) is a biocompatible scaffold with suitable mechanical properties (permeability, stability, elasticity, flexibility, resorbability and transparency), that is rich in stem cells and growth factors and is used for tissue repair and regenerative processes. It is routinely used in ocular surgery as it promotes epithelialization, supports cell adhesion and proliferation, and enhances wound healing. It exhibits both immunomodulatory and immunoregulatory properties, contributing to its anti-inflammatory and low immunogenicity risk profile. hAM transplantation is considered unlikely to trigger an immune response against human leukocyte antigens (HLA) and is generally regarded as minimally or non-immunogenic. This conclusion is primarily based on clinical observations, and a single study published 40 years ago that investigated subcutaneous hAM grafting-a procedure that does not reflect current clinical applications. Since then, there has been no laboratory evidence that hAM transplantation is immunologically safe. Notably, the production of anti-HLA antibodies following hAM transplantation has not been investigated, despite the tremendous improvements in the sensitivity of detection techniques. The recent application of hAM to more vascularized areas could raise concerns about potential immune responses. In this perspective paper, we summarize the limited and sometimes contradictory data regarding hAM immunogenicity. Then, we describe the methods we use to assess whether immune responses are triggered after hAM grafting in current clinical indications.