Lung transplantation, hand, skin and corneal transplantation

Organ donation. Transplant coordination and transplanted patients registry.

Posttransplant management. Immunosuppressive therapy.

Lung transplantation• The influence of HLA in lung transplantation is

open to debate.

• Donated lungs are allocated on the whole without consideration of HLA compatibility.

• Only when a potential recipient has been found to be sensitized to predefined HLA specificities, is the donor HLA type used to determine suitability.

• The poorer outcome of lung transplants compared to hearts is indicative of additional risk factors that help to mask other influences such as HLA.

• There are cases with no HLA mismatch, but with time, more cases where few HLA mismatches exist are gradually added.

• HLA mismatches have an influence on acute rejection as well as on the development of bronchiolitis obliterans syndrome.

• HLA-DR mismatch is commonly recognized as having the greatest influence.

Tissue typing• ABO match• Complete viral screening• HLA A, HLA B and HLA DRB1• PRA, crossmatch• TSH, T3, T4• PTH, calcitonine osteocalcin, vit.D, biochemistry,

tumor markers: CEA, CA 19-9, CA 125, AFP, β-HCG, α1-globulina

Skin transplantation

Skin transplantation• The principles of managing patients with severe

burns involve the maitenance of body homeostasis, nitrogen balance, immunocompetence and the exclusion of microorganism until nonviable tissue is removed and the wound safely closed.

• If the function of skin is not restored in a few weeks, the patient will die as a result of complex sequence of metabolic abnormalities and septic complications.

Skin transplantation

• In the absence of autologous skin, allograft skin (fresh human cadaveric skin) is the best biological membrane for burn wound coverage.

• Xenograft (porcine skin) – strong antigenity that leads to rapid rejection xenograft has to be removed on the third day after application.

• Human placental membranes – accelerate the healing process by exerting an angiogenic effect and increasing capillary density of the underlying wound bed.

Allograft skin• Used for temporary coverage of burn wounds.• Rejection of the grafts inevitably occurs after 2

weeks, despite of depressed immunity.• Prolongation of the allograft skin survival to

about 6 weeks could be achieved by pre-treating with steroids and UV light.

• The best match between donor and recipient is identity for HLA-A, B and DRB1.

• The use of cyclosporine prolongs the skin graft survival, but the rejection occurs within 2 weeks after treatment is stopped.

Hand transplantation(composite tissue allotransplatation)

Hand transplantation(composite tissue allotransplatation)

• A hand transplant, unlike a solid organ transplant, involves multiple tissues (skin, muscle, tendon, bone, cartilage, fat, nerves and blood vessels) and can be considered the “gold standard” in CTA.

• The world experience in human hand transplantation to date includes 50 transplants performed in 36 recipients. (www.handregistry.com)

Hand transplantation• The procedure is for individuals who have experienced

the difficult loss of a hand or forearm due to: (1) trauma; (2) life saving interventions that caused permanent injury to the hand or forearm.

• Hand transplant procedure is not being considered for: congenital anomaliesloss of a limb due to cancerleg amputations individuals whose injury is limited to fingers

Donated limbs would come from brain dead living donors.

Hand transplantation• The majority of patients demonstrated at least one

episode of acute rejection in the first year, and the skin was the primary target of the immune response.

• The high antigenicity of the skin can, in part, be related to the high proportion of potent antigen-presenting cells (Langerhans cells) and keratinocytes that express major histocompatibility complex (MHC) I constitutively, and MHC II, intercellular adhesion molecule 1 (ICAM)-I and proinflammatory cytokines upon stimulation.

• Viral infections, in particular cytomegalovirus (CMV), have been postulated to trigger the episodes of acute rejection

Corneal transplantation

Corneal transplantation• It is estimated that 10.000.000 people are

affected by various disorders that would benefit from corneal transplantation.

• 100.000 procedures are performed worldwide each year.

–UK: >2300 grafts/yr–Australia: 1500 grafts/yr–USA: > 40.000 people are corneal

transplanted

Corneal transplantationIndications:• Bullous keratopathy• Corneal degeneration• Corneal perforation• Keratoglobus and dystrophy• Scarring due to keratitis and trauma• Inflamed corneal tissue unresponsive to

antibiotics or anti-viral treatment

Corneal transplantationRisks:• Infection – the cornea has no blood vessels and

it heals much more slowly.• Graft failure – can occur at any time, even years

or decades later.

The role of HLA matching in reducing corneal graft failure could not be confirmed by all studies.

< 10% of primary grafts undergo immune rejection despite no routine HLA matching.

Corneal transplantation• HLA-A and HLA-B antigens have been identified on

corneal epithelium, stromal cells, corneal endothelial cells and are targets for CD8+ cytotoxic T cells.

• HLA-A and HLA-B matching was associated with improved outcome of corneal graft survival in high risk recipients.

• HLA-DR antigens are carried on Langerhans cells.• The role of HLA-DR matching in corneal transplantation

remains controversial.

• ABO incompatibility would lead to late corneal clouding

Immunosuppression

Immunosuppressive protocols in transplantation include the targeting of IL-2/IL-2R axis that are considered to be the most important pathway for T–cell proliferation.

Immunosuppressants classification•Calcineurin inhibitors:

Cyclosporine, Tacrolimus

•Antimetabolites:Mycophenolat mofetil, Azathioprina

•Corticosteroids

•Proliferation inhibitors (TOR-inhibitors):Sirolimus, Everolimus

Immunosupression

• Cyclosporin A: MEIA Axsym/TDx, HPLC• Tacrolimus: MEIA IMx, HPLC• Sirolimus: MEIA IMx, HPLC• Methotrexat: MEIA TDx

Interpatient Variability of CsA Absorption Not Captured by C-0

Adapted from Johnston A et al. Transplant Proc. 2000;32:53S-56S.

Extent and rate of absorption are highly variable.Patient differences are highlighted in the absorption phase.

Hours Post-Dose

0

200

400

600

800

1000

1200

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C-0 C-2

AUC0-4

AUC0-4

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Adapted from Halloran P et al. Transplantation.1999;68:1356-1361.

Sampling PointHours Post-Dose

0

20

40

60

80

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Calc

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Calcineurin Inhibition Maximal and IL-2 Suppression Most Consistent at 2 Hours Post-Dose

Sindhi R et al. Transplantation. 2000;69:432-436.

Kidney TransplantCyclosporinemia (ng/ml) CC00 Determination at 12 hours after administration:  

Month 1 250-350 ng/ml (preferably min 300 ng/ml)Month 2 – Month 3 250-300 ng/ml Month 4 – Month 12 250 ng/mlAfter 1 year 200-250 ng/ml

CC2 2 Determination at 2 hours after administration:  

Month 1 1600-1800 ng/ml Month 2 1400-1600 ng/ml Month 3 1200-1400 ng/ml After 1 year 700-800 ng/ml

TACROLEMIA (ng/ml)

• Day 1 - Day 7• Day 8 – Day 30• Day 31 – Day 60• Day 61 – Day 90• After 90 Days

• SIROLIMUS: 6 – 7 ng/ml

• 15 - 20 ng/ml• 10 – 20 ng/ml• 5 – 10 ng/ml• 5 - 10 ng/ml• 5 ng/ml

• HLA typing: Bone Marrow Tr. Unit Liver Tr. Unit Renal Tr. Unit Pancreatic islets Tr. Unit

National Bone Marrow Donor Registry Waiting list for - Bone Marrow tr. - Liver and Renal tr.

Romanian BMR • Started in 2003• EFI Accredited in 2006• Holds details of stem cell donors and cord

donations from Moldavia, Transilvania, Banat, Black Sea Coast, Walachia.

• We need to contiue to recruit more donors, particularly from ethnic communities

• HLA DNA 2 digits typed for HLA A, B, C, DRB1 and DQB1

Conclusions• Transplantation immunology is complex.

• Our Immunogenetic Centre provide expanded immunological monitoring together with virological and drug monitoring of the transplanted patients.

• Our goal is to offer complete integrated monitoring data and to fulfil EFI Standards.

• We are open for collaborative work and research projects within EFI.

• Clinical and laboratory scientists should work together as a team in order to have a complete overview of the transplanted patients.