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,
-HCG, 1-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 anomalies
loss of a limb due to cancer
leg 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 transplantation
Indications:
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 transplantation
Risks:
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 Tcell 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
1400
0 2 4 6 8 10 12
C-0 C-2
AUC
0-4

AUC
0-4

2
C-2
Adapted from Halloran P et al.
Transplantation.1999;68:1356-1361.
Sampling Point Hours Post-Dose
0
20
40
60
80
100
0
10
20
30
40
50
C-0 C-2 0
C-0
1 4
Calcineurin Inhibition Maximal and IL-2 Suppression Most
Consistent at 2 Hours Post-Dose
Sindhi R et al. Transplantation.
2000;69:432-436.
Kidney Transplant
Cyclosporinemia (ng/ml)

C
0

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/ml
After 1 year 200-250 ng/ml



C
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.