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Composite tissue Allografts
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Composite tissue allografts are highly immunogenic due to wide array of
tissue types especially skin and muscle
Possible now with newer agents
Rejection:
1. Hyperacute rejection (first 24 hours)
 Caused by preformed cytotoxic antibodies in recipient’s
plasma
 Usually bind to endothelium causing irreversible ischaemia
 Detect presurgery by incubating recipient’s plasma with
lymphoid tissue from donor
2. Acute rejection (usually >1 week)
 T cell mediated
 Foreign HLA antigens taken by antigen presenting cells and
presented to CD4+ T cells
 Clonal expansion of lymphocytes mediated by IL1,2,6
 Effectively treated by immunotherapy
2. Acute Vascular rejection (4-8 days)
 Seen in xenografts
 Characterized by endothelial activation and
coagulation, causing cell damage, thrombosis and eventual
graft rejection
 Treatment difficult – removal antibodies by plasmapheresis
or blobking antibody receptors by IV immunoglobulins
4. Chronic Rejection (years)
 characterized by graft arterial occlusions, which results
from the proliferation of smooth muscle cells and
production of collagen by fibroblasts.
 This process, termed accelerated or graft arteriosclerosis,
results in fibrosis within vessels and parenchyma
 No overt cause such as vascular injury or infection
 Hypothesized that chronic rejection is really the result of
continued prolonged multiple acute rejections
 Once developed, resistant to immunotherapy so need
lifelong maintenance therapy
3. Graft vs Host disease
 More a problem in bone marrow transplants
 Cytotoxic T and NK cells from donor initiate an immune
response against the recipient
 Develops a chronic autoimmune syndrome
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Strategies to avoid lifelong immunotherapy
1. tissue engineering
2. xenotransplantation
3. tolerance
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Tolerance may be achieved by
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1. bone marrow transplant – development of stable mixed allogeneic
chimerism
2. blockade of costimulatory molecules – anti-CD3 monoclonal antibodies
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Five basic categories of immunosuppressive agents:
1. corticosteroids
2. calcineurine inhibitors - cyclosporine, tacrilimus
3. antiproliferative agents - azathioprine, mycophenolate mofetil
4. monoclonal antilymphocyte antibodies – anti-CD25 (same as anti-IL2)
5. polyclonal antilymphocyte antibodies – antilymphocyte, antithymocyte
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Corticosteroids
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inhibit cytokine production, circulation of lymphocytes, acid metabolites,
and microvascular permeability (reduce oedema)
also block T cell activation and proliferation, and thus the clonal response.
Calcineurin inhibitors
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Cyclosporine – nephropathy and hypertension
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Tacrolimus is a modern variant of cyclosporine with less nephrotoxicity but
can cause CNS disturbances and diabetes. Also has a neuroregenerative
effect that makes it particularly useful in nerve transplants.
Antiproliferative agents
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Mycophenolate mofetil, a modern variant of azathioprine, is an antimitotic
agent that interrupts lymphocyte cell division. Its main side effects are
haematological, CMV infection and digestive toxicities (diarrhoea)
Antibody
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Polyclonal largely superceded. Most use anti-IL2 receptor antibodies
 IL-2 - released by helper T cells in response to an antigen and
interleukin-1. Stimulates the proliferation of T cells and NK cells
Drugs given as inductive, then maintenance therapy
Complications
Longterm side effects of the immunosuppressants fall into three categories:
1. opportunistic infections (cutaneous, fungal, and tinea infections, and
cytomegalovirus and herpes virus recurrences)
2. metabolic disorders (diabetes, Cushing’s syndrome)
3. Malignancies (basal cell and squamous cell carcinomas and EpsteinBarr virus B-cell lymphoproliferative disorders).