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Transplant Rejection and Its Treatment

Transplant Rejection and Its Treatment

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Published by arlindodascrot2011
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Published by: arlindodascrot2011 on Oct 30, 2010
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Transplant Rejectionand Its Treatment
R
ejection is the major cause of graft failure, and if the injury tothe tubules and glomeruli is severe, the kidney may not recover.It is therefore important to diagnose acute rejection as soon aspossible to institute prompt antirejection therapy. Generally, the successwith which rejection can be reversed by immunosuppressive agentsdetermines the chance of long-term success of the transplant [1,2].
Laurence Chan 
C H A PT ER
 
9.2
Transplantation as Treatment of End-Stage Renal Disease
Mechanisms of Renal Allograft Rejection
GraftdestructionAllograftAPC
CD8T cellsCD8T cellsCD4T cellsCD4T cells
Clonalexpansion
BcellsNK cellsCytokines
IL-2
IFN-
γ 
etc.
IL-1
HLA-classIHLA-classIHLA-classIHLA-classIIHLA-classIIHLA-classIICD3CD3CD3CD58CD58CD3CD2CD2CD2CD4CD4CD2CD8CD8TCRTCRTCRTCRIL-2RIL-2R
Immune response cascade
A
 
FIGURE 9-1
Aspects of the rejection response.
A,
The immune responsecascade. Rejection is a complex and redundant response to graftedtissue. The major targets of this response are the major histo-compatibility complex (MHC) antigens, which are designated ashuman leukocyte antigens (HLAs) in humans. The HLA region onthe short arm of chromosome 6 encompasses more than 3 millionnucleotide base pairs. It encodes two structurally distinct classesof cell-surface molecules, termed class I (HLA-A, -B, and -C) andclass II (-DR, -DQ, -DP).
B,
Overview of rejection events. T cells recognize foreign antigensonly when the antigen or an immunogenic peptide is associatedwith a self-HLA molecule on the surface of an accessory cell calledthe antigen-presenting cell (APC). Helper T cells (CD4) are activatedto proliferate, differentiate, and secrete a variety of cytokines. Thesecytokines increase expression of HLA class II antigens on engraftedtissues, stimulate B lymphocytes to produce antibodies against theallograft, and help cytotoxic T cells, macrophages, and natural killercells develop cytotoxicity against the graft.
C,
Possible mechanisms for allorecognition by host T cells. In thedirect pathway, T cells recognize intact allo-MHC on the surface of donor cells. The T-cell response that results in early acute cellularrejection is caused mainly by direct allorecognition. In the indirectpathway, T cells recognize processed alloantigens in the context of self-APCs. Indirect presentation may be important in maintainingand amplifying the rejection response, especially in chronic rejection.IFN-
—interferon gamma; IL-1—interleukin-1; IL-2R—inter-leukin-2 receptor; NK—natural killer. (
Panel A adapted from
[3];with permission;
 panel C adapted from
[4]; with permission.)
AllogeneiccellShedallogeneicMHCTaken up andprocessed by hostantigen-presenting cellCD8+cytotoxic cellCD8+cytoxic cellTh cellTh cellResponder antigen-presenting cell
Peptide derived fromallogeneic MHC presentedon host MHCAllogeneic (stimulator)antigen presenting cellClass IstimulatorClass IIhaplotypeClass IIIresponderhaplotype
β
2
microglobulinIL-2IL-2
(Class I–derived peptidepresented by responderclass II molecule)
Indirect allorecognitionDirect allorecognition
IIIIII
C
B.OVERVIEW OF REJECTION EVENTS
Antigen-presenting cells trigger CD4 and CD8 T cellsBoth a local and systemic immune response developCytokines recruit and activate nonspecific cells and accumulate in graft, which facilitatesthe following events:Development of specific T cells, natural killer cells, or macrophage-mediated cytotoxicityAllograft destruction
 
9.3
Transplant Rejection and its Treatment
Classification of Rejection
A.VARIETIESOF REJECTION
Types of rejection
HyperacuteAcceleratedAcuteChronic
B.IMMUNE MECHANISMSOFRENAL ALLOGRAFT REJECTION
Type
HyperacuteAcceleratedAcuteCellularVascularChronic
Humoral
+++++++++++
Cellular
-
++++++?
Time taken
Minutes to hoursDaysDays to weeksMonths to years
Cause
Preformed antidonor antibodies andcomplementReactivation of sensitized T cellsPrimary activation of T cellsBoth immunologic and nonimmunologicfactors
FIGURE 9-2
Varieties of rejection (
 panel A
) and immune mechanisms (
 panel B
).On the basis of the pathologic process and the kinetics of the rejectionresponse, rejection of renal allografts can be commonly dividedinto hyperacute, accelerated, acute, and chronic types.
AB
FIGURE 9-3
(
See
Color Plate)
Histologic features of hyperacute rejection. Hyperacute rejection isvery rare and is caused by antibody-mediated damage to the graft.The clinical manifestation of hyperacute rejection is a failure of thekidney to perfuse properly on release of the vascular clamps justafter vascular anastomosis is completed. The kidney initially becomesfirm and then rapidly turns blue, spotted, and flabby. The presenceof neutrophils in the glomeruli and peritubular capillaries in the kidneybiopsy confirms the diagnosis.
A
, Hematoxylin and eosin stain of biopsy showing interstitial hemorrhage and extensive coagulativenecrosis of tubules and glomeruli, with scattered interstitial inflam-matory cells and neutrophils.
B
, Immunofluorescence stain of kidneywith hyperacute rejection showing positive staining of fibrins.

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