Immune Responses to Tissue-Restricted Nonmajor Histocompatibility Complex Antigens in Allograft Rejection

Abstract

Chronic diseases that result in end-stage organ damage cause inflammation, which can reveal sequestered self-antigens (SAgs) in that organ and trigger autoimmunity. The thymus gland deletes self-reactive T-cells against ubiquitously expressed SAgs, while regulatory mechanisms in the periphery control immune responses to tissue-restricted SAgs. It is now established that T-cells reactive to SAgs present in certain organs (e.g., lungs, pancreas, and intestine) are incompletely eliminated, and the dysregulation of peripheral immuneregulation can generate immune responses to SAgs. Therefore, chronic diseases can activate self-reactive lymphocytes, inducing tissue-restricted autoimmunity. During organ transplantation, donor lymphocytes are tested against recipient serum (i.e., cross-matching) to detect antibodies (Abs) against donor human leukocyte antigens, which has been shown to reduce Ab-mediated hyperacute rejection. However, primary allograft dysfunction and rejection still occur frequently. Because donor lymphocytes do not express tissue-restricted SAgs, preexisting Abs against SAgs are undetectable during conventional cross-matching. Preexisting and de novo immune responses to tissue-restricted SAgs (i.e., autoimmunity) play a major role in rejection. In this review, we discuss the evidence that supports autoimmunity as a contributor to rejection. Testing for preexisting and de novo immune responses to tissue-restricted SAgs and treatment based on immune responses after organ transplantation may improve short- and long-term outcomes after transplantation.

Regenerative immunology: the immunological reaction to biomaterials

“…Moreover, the ECM functions as reservoir of proteins (cytokines and analogues) critical for the tissue's welfare that are released or stored depending on the tissue's metabolic needs. Interestingly, the ECM retains most of these factors throughout decellularization, a process by which ECM scaffolds are generated. This process, first described in the 1960s , aims to completely eliminate the cellular compartment of tissues and organs, including its DNA and RNA content, and can nowadays be successfully and consistently applied to virtually all mammal tissues and organs of clinical interest .…”

Acute rejection

“…Their group have introduced the concept of the 'two hit' hypothesis for the development SAGs. The initial 'hit' involves an initial lung injury as a result of triggers such as infections with community acquired respiratory viruses (CARV), gastro-oesophageal reflux disease (GORD), ischaemia-reperfusion injury, or even the presence of HLA-DSA (91,92). The resulting local inflammatory response exposes SAGs such as Col-V and Kα1T which stimulate up-regulation of self-reactive lymphocytes and non-HLA antibody production.…”

“…The second 'hit' is a result of down-regulation of regulatory T cells (TREGS) with loss of inhibition of self-reactive lymphocytes against SAGs which would usually induce T cell tolerance to SAGs. This ultimately leads to SAG autoimmunity Bharat (91,93). These SAGs may be a significant contributing factor to ongoing CLAD in patients who clear DSA post AMR treatment using commercially available kits that do not measure SAGs.…”

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

“…69,72,73,171 Although dogma states that self-reactive lymphocytes are deleted in the thymus, recent research has suggested that tissuerestricted SAgs are not expressed on thymocytes. 194 Therefore, it is the responsibility of Tregs to suppress self-reactive lymphocytes against tissue-specific SAgs. 194 It stands to reason that lung allograft injury, when combined with a loss of Tregs, would lead to lung-restricted autoimmunity (LRA).…”

“…194 Therefore, it is the responsibility of Tregs to suppress self-reactive lymphocytes against tissue-specific SAgs. 194 It stands to reason that lung allograft injury, when combined with a loss of Tregs, would lead to lung-restricted autoimmunity (LRA). Respiratory viral infections can injure pulmonary epithelium, downregulate Tregs, and result in de novo LRA.…”