Unlimited graft acceptance is hindered by allogenic immune responses.
CD4+ and
CD8+ T-lymphocytes along with other mononuclear leukocytes (their exact function regarding the topic is not known) participate in the rejection. These alloantibodies can activate the complement – this leads to target cell
lysis. Alternatively, donor cells are coated with alloantibodies that initiate
phagocytosis through Fc receptors of mononuclear leukocytes. The mechanism of humoral rejection is relevant for hyperacute, accelerated and chronic rejection. Alloimmunity can be also regulated by neonatal B cells. In addition to humoral immune responses, B-lymphocytes aid in T-cell activation by acting as antigen-presenting cells (APCs). TLOs also encourage a local alloimmune response needed for recovery and long-term health outcomes.
Cytokines Cytokine microenvironment where
CD4+ T-lymphocytes recognize alloantigens significantly influences polarization of the immune response. • CD4+ T-lymphocytes differentiate into
Th1 helper cells in the presence of
IL-12 (which is usually secreted by mature
dendritic cells). Th1 cells produce
proinflammatory cytokine IFN-γ and destroy the allograft tissue. • If there is
IL-4, CD4+ T-lymphocytes become
Th2 cells secreting IL-4 and
IL-5. •
TGF-β induces expression of
Foxp3 gene in the absence of proinflammatory cytokines and thus differentiation of CD4+ T-lymphocytes into
regulatory T cells (
Treg).
NK cells NK cells can also directly target the transplanted tissue. It depends on the balance of activating and inhibitory NK cell receptors and on their ligands expressed by the graft. Receptors of KIR (
Killer-cell immunoglobulin-like receptor) family bind concrete MHC class I molecules. If the graft has these ligands on its surface, NK cell cannot be activated (KIR receptors provide inhibitory signal). So if these ligands are missing, there is no inhibitory signal and NK cell becomes activated. It recognizes target cells by "missing-self strategy" and induces their apoptosis by enzymes perforin and granzymes released from its cytotoxic granules. Alloreactive NK cells also secrete proinflammatory cytokines IFN-γ and TNF-α to increase expression of MHC molecules and costimulatory receptors on the surface of APCs (
antigen-presenting cells). This promotes APC maturation which leads to amplification of T-cell alloreactivity by means of direct and also indirect pathway of alloantigen recognition (as described below). NK cells are able to kill Foxp3+ regulatory T-lymphocytes as well or by anti-inflammatory cytokine IL-10 and TGF-β secretion. However it is important to note that NK cell sub-populations differ in alloreactivity rate and in their immunomodulatory potential. Concerning
immunosuppressive drugs, the effects on NK cells are milder in comparison to T cells. •
Direct allorecognition – occurs when donor's APCs are presenting graft antigens. Recipient's T-lymphocytes can identify either MHC molecules alone or complex MHC molecule-foreign peptide as alloantigens. Specific
T-cell receptors (TCR) of CD8+ T-lymphocytes recognize these peptides when form the complex with MHC class I molecules and TCR of CD4+ T-lymphocytes recognize a complex with MHC class II molecules. •
Indirect allorecognition – recipient's APCs infiltrate transplanted tissue, then they process and present, as any other foreign peptides, donor's MHC glycoproteins by MHC class II molecules. Mechanism of indirect allorecognition and therefore the involvement of CD4+ T-lymphocytes is the main cause of graft rejection. That is why the compatibility between donor and recipient MHC class II molecules is the most important factor concerning transplantation.
Activation of T-lymphocytes T-lymphocytes are fully activated under two conditions: • T-lymphocytes must recognize complex MHC-alloantigen presented by APC through direct or indirect allorecognition pathway. • T-lymphocytes must receive costimulatory signal. There are costimulatory molecules on T-cell surface and APCs express their ligands (e.g. molecule CD28, which is on the surface of all naïve CD4+ and CD8+ T-lymphocytes, can bind ligands CD80 and CD86). Receptor-ligand engagement triggers T-cell signaling resulting in IL-2 production, clonal expansion and therefore development of effector and memory T-lymphocytes. In contrast, there are also such receptors on T-lymphocytes that cause inhibition of T-cell activation (for instance CD152/CTLA-4 receptor which binds CD80 and CD86 as well). If T-lymphocyte does not receive costimulatory signal, its activation fails and it becomes
anergic. Alloimmune response can be enhanced by proinflammatory cytokines and by CD4+ T-lymphocytes that are responsible for APC maturation and IL-2 production. IL-2 is crucial for
memory CD8+ T cell development. These cells may represent a serious problem after the transplantation. As the effect of being exposed to various infections in the past, antigen-specific T-lymphocytes have developed in patient's body. Part of them is kept in organism as memory cells and these cells could be a reason for "cross-reactivity" – immune response against unrelated but similar graft alloantigens. This immune response is called secondary and is faster, more efficient and more robust. ==Graft tolerance==