Page 1132 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1098 Part NiNe Transplantation

Trauma of transplantation antigens can also be significant, particularly in bone marrow
Organ retrieval, perfusion, and transplantation expression of transplantation (BMT), where activation of the adaptive immune
proinflammatory cytokines and recruitment of inflammatory cells into the graft system of the donor may result in graft-versus-host disease
(GvHD). These miH antigens may be derived from a wide variety
of polymorphic proteins and are encoded for a vast array of
Presentation of alloantigen to recipient T cells: genes distributed throughout the genome.
Direct, indirect, and semidirect presentation of alloantigen to recipient APC
Signal 1: Recognition of Alloantigen
Class I MHC molecules are cell surface glycoproteins expressed
T-cell activation:
TCR signal on most nucleated cells and are recognized by the T-cell receptors
Costimulation (TCRs) of CD8 T cells. Class II MHC molecules are not expressed
Cytokine generation by every cell in the body; rather they are found on DCs, B
lymphocytes, macrophages, and, in humans, endothelial cells.
MHC class II molecules are recognized by T cells bearing the
Cell-mediated immunity Th17 Humoral immunity CD4 surface glycoprotein. Expression of both class I and II MHC
Th1 Th2 molecules can be increased or, in the latter case, induced during
inflammation, in particular by IFN-γ.
Class I and II MHC proteins contain a highly polymorphic
groove or cleft, which can bind peptides, formed on a platform
of beta strands, flanked by two α helices. Antigen processing
T-cell migration: within antigen-presenting cells (APCs) results in the production
Upregulation of MHC and adhesion molecules attraction of peptides that can bind in these grooves producing a MHC–
of leucocytes into graft through chemotaxis peptide complex that can be recognized by T cells (Chapter 6).
These peptides may be of self origin or derived from foreign
molecules (e.g., from an allograft after transplantation or from
Graft destruction:
Infiltration of macrophages, cytokines, cytotoxic T cells, and a virus after an infection). In general, peptides derived from
antibodies leading to graft injury molecules present inside the cell are processed and loaded into
MHC class I molecules, whereas molecules present outside the
FiG 81.1 Mechanisms Leading to Graft Injury. Interplay of
innate and adaptive immune responses results in eventual graft cell in the extracellular environment are processed into peptides
destruction. that load into class II molecules. However, cross-presentation
can also occur, whereby some APCs, notably DCs, process
extracellular proteins such that they can be loaded onto MHC
class I molecules and presented to CD8 T cells, leading to
by interferon-γ (IFN-γ) produced by natural killer (NK) cells. “cross-priming.” 6
In one or more of these ways the innate immune system, activated The TCR is composed of two chains that confer MHC–peptide
by local tissue injury, promotes the initiation of adaptive immune specificity and is associated with a complex of polypeptides
responses when there are antigenic differences between the donor referred to collectively as CD3 (Chapter 4). On antigen recognition
and the recipient. Activation of the adaptive immune system by a TCR, CD3 delivers intracellular signals to the T cell (Chapter
results in a series of effector mechanisms, both cell and antibody 12). Recognition of antigen by the TCR–CD3 complex is the
mediated, that lead to further graft injury (Fig. 81.1). first step in T-cell activation and commonly referred to as “signal
A severely damaged graft will initiate a more aggressive 1.” This initial meeting between host naive and memory T cells
immune response, and this may explain the superior outcomes and alloantigen from the foreign transplant is believed to take
in living donor grafts compared with deceased donor grafts (as place in secondary lymphoid organs rather than in the transplanted
7
the former are subject to a lower degree of ischemic injury), graft itself. The inflammatory response triggered in the allograft
even in the presence of significant major histocompatibility by retrieval and implantation of the organ or tissue, as outlined
4
complex (MHC) mismatches. The immune response evoked above, not only initiates the migration of donor-derived passenger
by the damaged tissue also accounts for the higher rates of leukocytes but also their maturation into functional APCs
rejection observed in individuals with delayed graft function. 5 expressing high levels of donor MHC molecules.
The presentation of intact allogeneic MHC molecules by
Initiation of the Adaptive Immune System donor-derived passenger leukocytes to T cells is known as the
Recognition of differences between donor and recipient major direct pathway of allorecognition. This is the dominant pathway
and/or minor histocompatibility (miH) molecules or antigens through which the immune reaction to the graft is initiated, and
by T cells is central to the adaptive immune response. The T cells responding to direct antigen presentation constitute a
extensive polymorphism of MHC genes (Chapter 5) makes vast majority of the alloreactive immune repertoire, estimated
8
complete matching of unrelated individuals rare, and therefore, at 10% of T cells. After a time, the donor lymphocytes trans-
almost inevitably, transplantation of cells or organs between planted with the graft are depleted; however, this does not abrogate
genetically unrelated individuals occurs across an MHC mismatch. rejection. The immune response against an allograft is maintained
Knowledge of the MHC and of the structure of MHC molecules by recipient APCs, largely consisting of DCs and B cells, which
has contributed significantly to our understanding of how rejec- process and present peptides derived from allogeneic MHC
tion is triggered and has facilitated the development of novel molecules shed from the graft (soluble MHC molecules or
immunosuppressive drugs. Additionally, transplantation between apoptotic cells) as well as miH antigens. This route of allorecogni-
MHC-identical siblings has shown that differences in miH tion is known as the indirect pathway. Experimental models have