Alison Hines & Amy Foley

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barrier of transplantation today. Humoral and cell-mediated responses to specific antigens in donor tissue.

E.g. Human leukocyte antigens (HLA)

Hyperacute,

acute and chronic rejection.

The role of:

APCs T cells B cells Complement Platelets

Bone marrow Skin Intestine Islets of Langerhans Heart Kidney Liver

INCREASING IMMUNOGENICITY
Chang and Platt, 2009

HLA genes and corresponding MHC expression

Image adapted from Berestecky, 2007

Highly polymorphic Approximately 700 Class I alleles & 1000 class II alleles (Morales-Buenorostro, 2008) Likelihood of Ab formation related to number of differences between HLA triplets. Also related to differences in hydrophobicity and electrostatic charge between mismatched triplets.

Inflammation

Graft mechanical trauma. Image adapted from Titus et al, 2000 Reperfusion injury: Ischaemia & build up of toxic metabolites Release: Hageman Factor: damage control Fibrin & fibrinopeptides: clotting cascade, restore vascular integrity Bradykinin: vasodilation & increased vascular permeability Endothelial cells: Reduced expression of thrombomodulin and heparan sulphate proteoglycan. Increased expression of selectins and I-CAM-1. 0
Reviewed by Kirk & Strom, 2010

 Occurs

within 24hrs of reperfusion. Patients are presensitized to donor HLA antigens through previous transplants, pregnancy or blood transfusions. Presence of anti-HLA antibodies or antibodies directed against A & B blood groups. Characterised by:

Immediate loss of graft function Partial interstitial haemorrhage Microthrombi Inflammation

Pathogenesis
(Chang & Platt, 2009)

depends absolutely on activation of complement.

Image from: Janeway et al., 2001

Image from: Sacks et al., 2003

MAC Mechanism of tissue injury:

Influx of calcium activates endothelial cells. Surface expression of P-selectin & I-CAM-1. Platelets release pro-inflammatory cytokines (Ota et al., 2005). Granules in endothelial cells release vWF (Ota et al., 2005). Cell lysis Induces formation of intracellular gaps.

( Reviewed by Chang & Platt, 2009; Murata & Baldwin, 2009)

Direct:

Indirect:

Donor APC Donor MHC Self-peptide presented as foreign

Self APC Self MHC Donor MHC presented

Jiang et al., 2004 Image adapted from Lechler et al, 2005

Dendritic cells from donor organ move to lymph tissue. Dendritic cells stimulate CD4+ and CD8+ to undergo activation and clonal expansion. CD4+ cells release IL-2, IL-4, IL-13 and IFN-.

Graft destruction occurs via:

CTL Cytokines Recruitment of macrophages and eosinophils B cell Ab production

Image adapted from Lechler et al, 2005

Two roles in acute rejection

1. 2.

Antibody production Antigen presenting cell

1.

Antibody alone is poor at promoting acute rejection, but contributes to targeting graft cells for destruction (Chang & Platt, 2009). Research has shown that anti-CD20 antibody, together with anti-T cell and cytotoxic drugs, reduces allograft rejection (Zarkhin et al, 2008). In the presence of chronic exposure to low levels of donor antigen, B cells evolve as efficient antigen presenting cells, expressing HLA antigens, driving T cell mediated rejection.
Detection of C4d is part of the Banff classification system for diagnosis of humoral rejection in the kidney (Racusen et al, 2003).

2.

Time scale: From one year after graft transplant. Recognition of mismatched donor HLA antigens is the critical for initiating chronic rejection (Kaczmarek et al., 2008). Presence of anti-HLA Ab is strongly associated with chronic allograft rejection of heart and kidney grafts (Jindra et al, 2008) Slow and steady graft destruction, characterised by occlusion of arteries and veins over time (Nath et al, 2010). Extensive growth of neointima causing occlusion and vascular insufficiency, ischemia, tissue damage and necrosis and fibrosis (reviewed by Chang & Platt, 2009).

Bronchiolitis obliterans (BOS) in lung grafts Cardiac allograft vasculopathy (CAV) in heart grafts Chronic allograft nephropathy (CAN) in kidney grafts

Einecke et al. (2009), provided robust evidence that anti-HLA antibodies are a major cause (63%) of chronic rejection. Direct role of anti-MHC Class I in pathogenesis of BOS (Kuo et al., 2005). Antibodies against minor antigens, such as H-Y, form when females receive male kidney transplant (Tan et al, 2008) Antibodies to self-antigens lead to autoimmunity and associate with poor allograft outcome (Seetharam et al, 2010): K-alpha-1-tubulin & collagen-V (lung), Collagen-V (lung) Many BOS patients develop Abs reactive to K-alpha-1tubulin, an epithelial cell Ag (Goers et al, 2008). Angiotensin II type 1 receptor (kidney) Myosin (heart)

Formation of ectopic functional germinal centres (tertiary lymphoid tissue). Expression of the key enzyme activationinduced cytidine deaminase (AID), allows the B cell to undergo class switching (reviewed in Deteix et al, 2010). The specificities of circulating Ab are different to locallyproduced Ab. Locally-produced has higher diversity (Thaunat et al, 2010). Memory B and plasma cells are generated close to the target. This provides an aggressive response which may be difficult to control by standard therapies. Thaunat et al found that B cells from tertiary lymphoid tissue could survive anti-CD20 antibody therapy, when circulating B cells were depleted.

Image from Deteix et al, 2010

A recent study by Deteix et al., found Th17 infiltration was significantly associated with shorter graft survival of kidney grafts. Th17 presence was increased in the fast progressing chronic rejection group, and T regs were barely detectable. In contrast, T reg presence was increased in the slow progressing group, and Th17 levels were reduced. Th17 produces IL-17 and IL-21. A significant increase in IL-21 expression was found in fast progressing group. IL-21 directly promotes the activation and differentiation of B cells. B cells were expressing AID functional germinal centres. The correlation between AID and IL-21 could mean that Th17 increases graft destruction by promoting lymphoid neogenesis.

There are antigen dependent and antigen independent mechanisms of graft allorecognition MHC: major antigen driving rejection Three types of rejection which are characterized by:

Time scale Cell involvement Complement mediated graft destruction

Hyperacute rejection:

Acute rejection:

Predominantly T cell mediated involving for example, eosinophils and macrophages

Characterized by a fibrous occlusion and formation of tertiary lymphoid tissue Chronic rejection mechanisms Prognosis and therapy

Chronic rejection:

What is the future:

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