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4
Vascularized Composite
Allotransplantation
Sherry Tang
OVERVIEW
DEFINITIONS
Vascularized composite allografts (VCAs) or composite
tissue allografts are “composite” grafts made of multiple tissue
types that are transplanted together as a single functional unit.
This may consist of skin, bone, tendon, muscle, nerves, vessels,
and fat.
Autotransplantation: Tissues of an individual are moved to
another location on the same individual.
Allotransplantation: Tissues are transplanted from one
individual to another individual of the same species.
TRANSPLANTATION IMMUNOLOGY
Alloimmune Response
Major histocompatibility complex (MHC) and human
leukocyte antigens (HLAs)
MHC complex is a cell surface glycoprotein that
functions to distinguish between self- and non–selfantigens. It plays an important role in the alloimmune
response and adaptive immunity.
Two classes: MHC class I and MHC class II.
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MHC class I molecules are expressed on all
nucleated cells.
HLA-A, HLA-B, HLA-C
MHC class II molecules are only expressed on
antigen-presenting cells (APCs).
HLA-DP, HLA-DO, HLA-DR
Each MHC is associated with a group of HLA genes,
which determine the compatibility of all organ and
tissue transplants.
Initiation of an alloimmune response
Dendritic cells (DCs), which are APCs in the peripheral
tissue, first acquire donor antigen in the peripheral
tissues and express donor MHC alloantigen on their
cell surface.
DCs then migrate to lymphoid tissue via lymphatics,
where the donor MHC alloantigen that is on the surface
of DCs interacts with T-cell receptors (TCRs) on the
recipient naive T cell. In addition, a CD3 complex
facilitates this interaction between DCs and T cells,
forming signal 1.
APCs also provide costimulatory signals, referred to as
signal 2, to fully activate T cells. The B7/CD28 and
CD40/CD154 pathways are two costimulatory signal
pathways in transplantation.
Once a naive T cell receives both signal 1 and signal 2,
intracellular signal transduction pathways are activated,
which leads to increased expression of cytokines that
initiate T-cell proliferation and development of effector
T cells. This is referred to as signal 3.
T regulatory cells
CD4+CD25+FoxP3+ cell population
May be induced or native (derived in thymus)
Inhibit effector T cells, mitigating rejection or graft vs
host disease
Express cytotoxic lymphocyte antigen 4 (CTLA4).
CTLA4 can bind to costimulatory molecules (CD80
and CD86) to activate indoleamine 2,3-
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dioxygenase (IDO) to deprive local environment of
tryptophan and produce kynurenines, attenuating
T-cell proliferation.
Produces IL-10 (immunosuppressive cytokine),
which inhibits APC activity and promotes T-cell
conversion to T regulatory cells.
Believed to exert their effects in the lymph node and
allograft.
*Types of Rejection
Hyperacute rejection occurs within minutes to hours after
transplantation. It is mediated by preexisting antibodies to
HLA or ABO antigens. Can lead to microthrombi, vascular
occlusion, and necrosis of allograft.
Acute rejection occurs in days to weeks after
transplantation. It is caused by HLA mismatch and
mediated by effector T cells.
Chronic rejection occurs in months to years after
transplantation and is the major cause of long-term graft
loss. It is characterized by intimal proliferation of vessels,
skin and muscular atrophy, and fibrosis of deep tissues.
Skin Immunogenicity in VCA
Skin is a major component of most VCA grafts.
Skin is the most immunogenic of all types of a tissue due
to a higher presence of effector T cells and the ability for
endothelial cells to recruit immune cells and upregulate
MHC class II molecule, inflammatory markers,
costimulatory, and vasoactive molecules.
Approximately 80% of all face and upper extremity
transplants have signs of acute rejection within 1 year,
compared to 10% in kidney transplants.
Acute rejection appears to affect the skin first. It
manifests as erythematous macules and diffuse redness.
Histologic analysis shows lymphocytic infiltrate consisting of
T cells. It is graded according to the Banff score (Table 4-
1).
Treatment: Increase oral or IV steroids, polyclonal or
monoclonal antibodies, and topical
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immunosuppressants.
TABLE 4-1 Banff Score for Acute Rejection
Split tolerance phenomenon has been reported, in which
there is rejection of the skin but no other types of tissue
within the graft.
Immunosuppression
Immunosuppression medications are required to prevent
both acute and chronic rejection. The immunosuppressive
protocols used for VCA are based on those used in solid
organ transplantation.
Two phases of immunosuppression
Induction immunosuppression uses polyclonal
antithymocyte antibody and basiliximab to deplete
recipient T cells.
Maintenance immunosuppression uses a triple therapy
with tacrolimus, mycophenolate mofetil, and
prednisone.
Risks associated with immunosuppression
Tacrolimus is associated with elevated serum
creatinine levels.
Prednisone is associated with hypertension, diabetes,
dyslipidemia, and risk of malignancy.
Opportunistic infection including CMV, EBC, HSV,
Pneumocystis jirovecii, bacterial, and fungal infections.
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Minimization protocols using tacrolimus and mycophenolate
have been studied, but this is associated with increased
acute rejection episodes.
Topical tacrolimus and clobetasol have been successful
in treating lower-grade rejection (Banff grades 1-2). Some
animal studies have demonstrated that topical
immunosuppression can be superior to systemic
immunosuppression in certain cases.
Tolerance induction is an area of active research in preclinical
models. It relies on achieving mixed chimerism, in which the
immune cells of both recipient and donor can exist in the
recipient without destructive immunologic responses.
Donor hematopoietic stem cells (HSCs) are isolated from
the donor bone marrow.
The recipient is conditioned using whole-body irradiation, Tcell depletion, and costimulatory blockade.
Donor HSCs are injected into the recipient and migrate to
the thymus, where both recipient and donor cells undergo
clonal deletion to achieve central tolerance.
Stable engraftment of donor HSCs ensures mixed
chimerism and allows tolerance of donor VCAs.
Graft vs Host Disease (GVHD)
Multisystem complication associated with HSC
transplantation and has been observed in VCA when
combined with stem cell transplants in preclinical models.
Donor T cells attack the host.
Clinical findings
Acute GVHD: onset <100 days. Maculopapular rash,
abdominal pain with diarrhea, elevated serum bilirubin.
Chronic GVHD: onset >100 days. May resemble
autoimmune disorders. GI sclerosis, elevated bilirubin,
skin manifestation such as cutaneous scleroderma,
bronchiolitis obliterans.
Ischemia-Reperfusion Injury
Maximum ischemic time has not been established for VCAs
but prolonged ischemic time can negatively impact success.
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Prolonged ischemia followed by reperfusion results in
production of reactive oxygen species, which leads to
oxidization of proteins and upregulation of heat shock
proteins.
Heat shock proteins activate toll-like receptors and may
mediate innate immune responses.
TYPES OF ALLOTRANSPLANTATION
IN PLASTIC SURGERYHAND AND
UPPER EXTREMITY
TRANSPLANTATION
Background
The first hand transplantation was performed in Ecuador in
1964, ending in rejection 2 weeks postoperatively.
Subsequent hand transplant in France in 1998 lost after 2.5
years due to medication noncompliance.
Over 150 upper limb transplants in 100 patients in 45
centers worldwide since 1998.
Indications and Patient Selection
Unilateral or bilateral upper limb loss causing significant
loss of quality of life.
Age over 18. Some centers may consider pediatric patients
at a minimum of age 8 years with bilateral upper limb loss.
Trial of prostheses.
Lack of significant coexisting medical or psychosocial
issues.
Patient must demonstrate compliance, motivation, and
ability to successfully manage a VCA allograft.
ABO crossmatch is performed; however, most hand
transplants to date have been performed despite HLA
mismatch.
Surgical Procedure
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Surgical planning
Requires a multidisciplinary team consisting of plastic,
orthopedic and transplant surgery, transplantation
medicine, anesthesiology, organ procurement
organization, nursing, occupational and physical
therapy, psychology, and social work.
Surgical rehearsals, check lists, and adjunctive
planning tools such as CT virtual surgical planning and
3D printer models are useful.
Donor procedure
Donor limb evaluation: limb and bone size, skin color
and tone, gender, absence of tattoos, limb quality
(trauma, joint mobility, vessel patency, age).
Upper extremity procurement from deceased donor
requires amputation of the allograft proximal to the
level of the defect in the recipient.
The amputated allograft is flushed with cold
preservation solution to avoid warm ischemia, wrapped
in moist sterile gauze, placed in a sealed plastic bag,
and transported on ice in a cooler.
A prosthesis is fitted to the deceased donor to avoid
donor disfigurement after amputation of the allograft.
Deceased donor will also likely be donor for solid
organs so careful coordination with solid organ
transplant procurement team(s) is required.
Once back at the recipient operation room, all key
structures are identified and tagged.
Recipient procedure
The recipient stump is dissected under tourniquet and
the bony stump is prepared. All key structures are
identified and tagged.
Transplantation then proceeds in the order of bony
fixation, tendon/muscle repair, nerve repair, and
vascular repair. Depending on the level of transplant
and cold ischemia time, vascular repair can be
performed earlier to avoid ischemia-reperfusion injury.
Rehabilitation
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Rehabilitation is similar to that after replantation. Generally,
begin therapy within 2-3 days after surgery with passive
motion and custom splint fitting. Active motion may be
started within weeks after surgery. Therapy is intense
during the first year and then gradually taper.
Steroid use as part of immunosuppression impedes healing
and may place tendon repair at risk if active motion is
started too early postoperatively.
Outcomes
Patient survival rate for isolated unilateral or bilateral hand
transplantations: 96.7% at 1, 5, and 10 years after
transplantation
Graft survival rate: 90.4% at 1 year and 86.6% at 5 and 10
years
Functional outcome
Standardizing functional outcome measures is
challenging due to nonuniversally agreed outcomes
measures, the variability in levels of transplantation,
and the long time required to reach maximal functional
improvement.
Outcome measures include the Hand Transplant
Scoring System, the Sollerman test, and the
Disabilities of the Arm, Shoulder, and Hand test.
In general, more distal transplants have the best
absolute function with sensory and motor recovery.
International Registry on Hand and Composite Tissue
Transplantation report in 2010
All patients developed protective sensation, 90%
developed had protective sensibility, and 84% had
discriminative sensibility.
Majority developed intrinsic muscle reinnervation
at 9-15 months postoperatively.
Quality of life reported to be improved in 75% of
patients.
Hand and upper extremity transplantations are no longer
considered “experimental.” With the appropriate patient
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selection, this can be considered the most suitable
treatment.
FACE TRANSPLANTATION
Background
First face transplant in November 2005 in France.
More than 40 face transplantations documented worldwide
since 2005.
Indications and Patient Selection
No consensus on inclusion and exclusion criteria.
Assessment tools such as the Cleveland Clinic FACES
Score have been developed to identify ideal candidates.
Significant facial deformity after conventional autologous
reconstruction has been tried with unsatisfactory results.
Facial deformity has been due to trauma (animal bites,
gunshot wounds), congenital deformities, burns, and cancer
defects. Gun shot and burn patients make up 2/3 of all face
transplant recipients.
Consideration has been given to skin color and HLA
matching.
Surgical Procedure
Surgical planning
CT or MRI help determine amount of missing tissue.
Dental occlusion and orthognathic planning can help
determine facial width and position.
Donor procedure
Surgical procedure is dependent on the structures
required for transplantation.
May include bone, muscle, nerve, mucosa, and
skin.
May include various aesthetic units, including
nose, lips, and cheeks.
Facial artery or external carotid arteries are used as
pedicles.
Facial nerve is transected at the level of the facial
nerve trunk or more distally to perform neurorrhaphy
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with the recipient facial nerve.
Ischemia time ideally <4 hours, but no proven
correlation between prolonged ischemia time and
frequency of acute rejection episodes.
Recipient procedure
Recipient vessels and facial nerve trunks are identified.
Microvascular anastomosis performed between donor
and recipient vessels.
Facial nerves are connected.
Sensory nerves (eg, trigeminal branches) are
connected if available.
Rehabilitation
Facial muscle reeducation, speech, and swallow therapy
start immediately after surgery.
Outcomes
Patient survival rate: 96.6% at 1 year and 96.2% at 5 years
Graft survival rate:
96.6% at 1 and 5 years
80% of patients have at least one episode of acute
rejection within the first year with the majority of
rejections episodes being steroid sensitive
Functional outcome
No standard functional outcomes measure given
variability in injuries and face transplant protocols.
Functional success is determined by restoration of
breathing, eating, tasting, smelling, talking, facial
expressions, and sensation.
Motor recovery detectable 6-8 months after
surgery.
Sensory recovery detectable as early as 3 months
after surgery.
Improvement in quality of life is variable and is
influenced by pretransplant mental disorder and
risk factors.
Most patients are able to accept their new faces
without issues relating to facial identity. However,
lack of acceptance of the transplanted face
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