E3 7 Transplant Rejection PDF

The growing allogeneic organ supply/demand imbalance has resulted in an expanding transplant waiting list. Sykes and Sachs, Sci. Immunol. 4, eaau6298 (2019) 4  First- and second-set allogr...

The growing allogeneic organ supply/demand imbalance has resulted in an expanding transplant waiting list. Sykes and Sachs, Sci. Immunol. 4, eaau6298 (2019) 4  First- and second-set allograft rejection These experiments established that the failure of skin grafting was caused by an inflammatory reaction, which was called rejection. The knowledge that graft rejection is the result of an adaptive immune response came from experiments demonstrating that the process had characteristics of memory and specificity and was mediated by lymphocytes Transplantation of cells or tissues from one individual to a genetically nonidentical individual invariably leads to rejection of the transplant because of an adaptive immune response. This problem was first appreciated when attempts to replace damaged skin on burn patients with skin from unrelated donors proved to be uniformly unsuccessful. Within 1 to 2 weeks, the transplanted skin would undergo necrosis and fall off. 5  The genetics of graft rejection The basic rules of transplantation immunology, which were first established from experiments done with genetically defined mice, include the following:  Cells or organs transplanted between genetically identical individuals (identical twins or members of the same inbred strain of animals) are not rejected.  Cells or organs transplanted between genetically nonidentical people or members of two different inbred strains of a species are almost always rejected.  The offspring of a mating between two different inbred strains of animal will not reject grafts from either parent. In other words, an (A × B) F1 animal will not reject grafts from an A or B strain animal. (This rule is violated by HSC transplantation, when natural killer (NK) cells in an (A × B) F1 recipient do reject HSCs from either parent, as we will discuss later in this chapter.)  A graft derived from the offspring of a mating between two different inbred strains of animal will be rejected by either parent. In other words, a graft from an (A × B) F1 animal will be rejected by either an A or a B strain animal 6  T Lymphocyte Maturation in the Thymus  Negative selection is the process that eliminates developing lymphocytes whose antigen receptors bind strongly to self-antigens present in the generative lymphoid organs. The cell death (Apoptosis) is due to a combination of factors, including:  Failure to productively rearrange the TCR β chain gene and thus to fail the pre-TCR/β,  Failure to be positively selected by self MHC molecules in the thymus,  Self antigen–induced negative selection. 7  MHC Genes  The polymorphic class I and class II MHC molecules are the ones whose function is to display peptide antigens for recognition by CD8+ and CD4+ T cells, respectively.  The products of different MHC alleles bind and display different peptides, different individuals in a population may present different peptides even from the same protein antigen.  For a given MHC gene, each individual expresses the alleles that are inherited from both parents. For the individual, this maximizes the number of MHC molecules available to bind peptides for presentation to T cells. 8 Map Of The Human MHC Genes In humans, the MHC is located on the short arm of chromosome 6 and occupies a large segment of DNA, extending about 3500 kilobases (kb) There are three class I MHC genes called HLA-A, HLA-B, and HLA-C, which encode three types of class I MHC molecules with the same names. There are three class II HLA gene loci called HLA-DP, HLA-DQ, and HLA-DR. Each class II MHC molecule is composed of a heterodimer of α and β polypeptides. The set of MHC alleles present on each chromosome is called an MHC haplotype. 9  Direct and indirect alloantigen recognition Allogeneic MHC molecules of a graft can be presented for recognition by the recipient’s T cells in two different ways, called direct and indirect. Initial studies showed that the T cells of a graft recipient recognize intact, unprocessed MHC molecules in the graft, and this is called direct presentation (or direct recognition) of alloantigens. Subsequent studies showed that sometimes the recipient T cells recognize graft (donor) MHC molecules only in the context of the recipient’s MHC molecules, implying that the recipient’s MHC molecules must be presenting peptides derived from allogeneic donor MHC proteins to recipient T cells. This process is called indirect presentation (or indirect recognition), and it is essentially the same as the recognition of any foreign (e.g., microbial) protein antigen 10  Molecular basis of direct recognition of allogeneic MHC molecules  MHC molecules that are expressed on cell surfaces normally contain bound peptides, and in some cases the peptide contributes to the structure recognized by the alloreactive T cell, exactly like the role of peptides in the normal recognition of foreign antigens by self MHC–restricted T cells.  Even though these peptides may be derived from proteins that are present in both donor and recipient, on the graft cells they are displayed by allogeneic MHC molecules.  Therefore, the complexes of peptides (self or foreign) with allogeneic MHC molecules will appear different from self peptide–self MHC complexes.  In other cases, direct recognition and activation of an alloreactive T cell may occur regardless of which peptide is carried by the allogeneic MHC molecule, because the polymorphic amino acid residues of the allogeneic MHC molecule alone form a structure that resembles self MHC plus peptide 11  Activation of alloreactive T cells  The T cell response to an organ graft may be initiated in the lymph nodes that drain the graft.  Most organs contain resident APCs, such as DCs, and therefore transplanted organs carry with them APCs that express donor MHC molecules.  These donor APCs can migrate to regional lymph nodes and present, on their surface, unprocessed allogeneic class I or class II MHC molecules to the recipient’s CD8+ and CD4+ T cells, respectively (direct MHC allorecognition).  Host DCs from the recipient may also migrate into the graft, pick up graft alloantigens, and transport these back to the draining lymph nodes, where they are displayed (the indirect pathway). 12 Hyperacute rejection Hyperacute rejection is characterized by thrombotic occlusion of the graft vasculature that begins within minutes to hours after host blood vessels are anastomosed to graft vessels and is mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens 13 Acute cellular rejection The principal mechanisms of acute cellular rejection are CTL-mediated killing of graft parenchymal cells and endothelial cells and inflammation caused by cytokines produced by helper T cells 14  Acute antibody mediated rejection  Alloantibodies cause acute rejection by binding to alloantigens, mainly HLA molecules, on vascular endothelial cells, leading to endothelial injury and intravascular thrombosis that result in graft destruction.  The binding of the alloantibodies to the endothelial cell surface triggers local complement activation, which causes lysis of the cells, recruitment and activation of neutrophils, and thrombus formation.  Alloantibodies may also engage Fc receptors on neutrophils and NK cells, which then kill the endothelial cells. In addition, alloantibody binding to the endothelial surface may directly alter endothelial function by inducing intracellular signals that enhance surface expression of proinflammatory and procoagulant molecules. 15  Chronic rejection  A dominant lesion of chronic rejection in vascularized grafts is arterial occlusion as a result of the proliferation of intimal smooth muscle cells, and the grafts eventually fail mainly because of the resulting ischemic damage.  The arterial changes are called graft vasculopathy or accelerated graft arteriosclerosis.  Graft vasculopathy is frequently seen in failed cardiac and renal allografts and can develop in any vascularized organ transplant within 6 months to a year after transplantation.  The likely mechanisms underlying the occlusive vascular lesions of chronic rejection are activation of alloreactive T cells and secretion of IFN-γ and other cytokines that stimulate proliferation of vascular smooth muscle cells.  As the arterial lesions of graft arteriosclerosis progress, blood flow to the graft parenchyma is compromised, and the parenchyma is slowly replaced by nonfunctioning fibrous tissue 16 Biologic actions of IL-2 A, Interleukin-2 (IL-2) stimulates the survival, proliferation, and differentiation of T lymphocytes, acting as an autocrine growth factor, leading to the generation of effector and memory cells. B, IL-2 also promotes the survival of regulatory T cells and maintains their functional capability, and thus controls immune responses (e.g., against self antigens). TCR, T cell receptor.  Autocrine  Paracrine  Endocrine 18 The Immune Synapse 19  The Immune Synapse The synapse forms a stable contact between an antigen- T Cell specific T cell and an APC displaying that antigen and becomes the site for assembly of the signaling machinery of the T cell, including the TCR complex, coreceptors, costimulatory receptors, and adaptors. The immune synapse provides a unique interface for TCR triggering, thus facilitating prolonged and effective T cell signaling. The synapse ensures the specific delivery of secretory granule contents and cytokines from a T cell to APCs or to targets that are in contact with the T cell. The synapse, may also be an important site for the turnover of signaling molecules. This degradation of signaling proteins contributes to the termination of T cell activation. APC 20 T cell signaling 21 Mechanisms of action of immunosuppressive drugs 22 Mechanisms of action of immunosuppressive drugs 23 Mechanisms of action of immunosuppressive drugs 24  Corticosteroids switch on anti-inflammatory gene expression Corticosteroid activation of anti-inflammatory gene expression. Corticosteroids bind to cytoplasmic glucocorticoid receptors (GRs) that translocate to the nucleus, where they bind to glucocorticoid response elements (GREs) in the promoter region of steroid- sensitive genes and also directly or indirectly to coactivator molecules such as cAMP-response-element-binding-protein- binding protein (CBP), p300/CBP-associated factor (pCAF) or steroid receptor coactivator (SRC)-2, which have intrinsic histone acetyltransferase (HAT) activity, causing acetylation of lysines on histone H4, which leads to activation of genes encoding anti- inflammatory proteins, such as secretory leukoprotease inhibitor (SLPI), mitogen-activated protein kinase phosphatase (MKP)-1, inhibitor of nuclear factor-κB (IκB-α) and glucocorticoid-induced leucine zipper protein (GILZ). ↑: increase. European Respiratory Journal 2006 26  Corticosteroids switch off inflammatory genes  Corticosteroid suppression of activated inflammatory genes. Inflammatory genes are activated by inflammatory stimuli, such as interleukin (IL)-1β or tumour necrosis factor (TNF)-α, resulting in activation of inhibitor of I-κB kinase (IKK)2, which activates the transcription factor nuclear factor (NF)-κB.  A dimer of p50 and p65 NF-κB translocates to the nucleus and binds to specific κB recognition sites and also to coactivators, such as cAMP-response-element-binding-protein-binding protein (CBP) or p300/CBP-associated factor (pCAF), which have intrinsic histone acetyltransferase (HAT) activity.  This results in acetylation of core histone H4, resulting in increased expression of genes encoding multiple inflammatory proteins. Glucocorticoid receptors (GRs), after activation by corticosteroids, translocate to the nucleus and bind to coactivators in order to inhibit HAT activity directly and recruiting histone deacetylase (HDAC)2, which reverses histone acetylation, leading to suppression of these activated European Respiratory Journal 2006 inflammatory genes. ↑: increase; -: suppression. 27 Immunosuppressive drugs 28 ABO blood group antigens 29  Immunologic Complication of Hematopoietic Stem Cell Transplantation Histopathology of acute GVHD  HSC transplantation is a clinical procedure to treat lethal diseases in the skin caused by intrinsic defects in one or more hema­topoietic lineages in a patient.  A patient’s own hemato­poietic cells are destroyed, and HSCs from a healthy  donor are then given to restore normal blood cell produc­tion in the patient.  HSC transplantation is most often used clinically in the treatment of leukemias and pre­leukemic conditions.  Allogeneic HSCs are rejected by even a minimally immunocompetent host, and therefore, the donor and recipient must be carefully matched at all MHC loci.  GVHD is caused by the reaction of grafted mature T cells in the HSC inoculum with alloantigens of the host.  The consequence of immunodeficiency is that HSC transplant recipients are susceptible to viral infections, especially cytomegalovirus, bacte­rial and fungal infections.  They are also susceptible to Epstein­Barr virus–provoked B cell lymphomas. 31  Induced Pluripotent Stem (iPS) cells  There is great interest in the use of pluripotent stem cells to repair tissues that have little natural regenerative capacity, such as cardiac muscle, brain, and spinal cord.  The major barrier to their successful grafting embryonic stem cells will be their alloantigenicity and rejection by the recipient’s immune system.  A possible solution to this may be to use induced pluripotent stem (iPS) cells, which can be derived from adult somatic tissues by transduction of certain genes.  The immunologic advantage of the iPS cell approach is that these cells can be derived from somatic cells har­vested from the patient, and therefore they will not be rejected.  Another solution now being investigated is to remove MHC genes from allogeneic embryonic stem cells by CRISPR­Cas9 genome editing technology. 32 Generation of chimeric antigen receptor regulatory T cells (CAR Tregs). + 35 Genetic modifications that have been made in pigs to facilitate pig-to-human organ transplantation 37