2.
3
Edgardo P. Penserga, M.D.
“Don't think of organ donations as giving up part of yourself to keep a total stranger alive. It's
really a total stranger giving up almost all of themselves to keep part of you alive.” ~Anonymous
Objectives:
 To know the basic principles behind organ transplantation
 To know the basic immunology of transplantation
TOPIC Page No.
History
Terminology
Recipients
Donors
Organ Transplantation
Indications of Organ
Transplantation
Criteria for Organ Transplantation
Brain Death
Evaluation of Potential Donors
Management of Donors
Procurement, Protection and
Preservation of Organ Donors
Immunology of Transplantation
Clinical Types of Organ Rejection
Immunosuppression in
Transplantation
HISTORY
 Organ transplant is not a recent development dating to
centuries B.C.
 In recent years, the transplant success is boosted with
improvement in immunology and development of more
effective anti-rejection drugs
PERSONALITIES IN ORGAN TRANSPLANTATION
 The Chinese physician Pien Chiao reportedly exchanged
hearts between a man of strong spirit but weak will with
one of a man of weak spirit but strong will in an attempt to
achieve balance in each man
 Roman Catholic accounts report the 3rd century saints
Damian and Cosmas as replacing the gangrenous leg
of the Roman deacon Justinian with the leg of a recently
deceased Ethiopian.
 The more likely accounts of early transplants deal with
skin transplantation. The first reasonable account is of
the Indian surgeon Sushruta in the 2nd century BC, who
used auto grafted skin transplantation in nose
reconstruction, a rhinoplasty
 The first successful corneal allograft transplant was
performed in 1837 in a gazelle model; the first successful
human corneal transplant, a keratoplastic operation,
was performed by Eduard Zirm at Olomouc Eye Clinic, now
Czech Republic
 In 1905, the first transplant in the modern sense- the
implantation of organ tissue in order to replace an
organ function – was a thryroid transplant in 1883. It was
performed by the Swiss surgeon and later Nobel laureate
Theodor Kocher.
 In the preceding decades Kocher had perfected the
removal of excess thyroid tissue in cases of goiter to an
extent that he was able to remove the whole organ
without the patient dying from the operation. He
carried out the total removal of the organ in some cases as
a measure to prevent recurrent goiter
Agatep. Detera. Doong. Rodriguez. Tejano. Villacorta
August 29,2013
Organ Transplantation
& Immunology
 By 1883, the surgeon noticed that the complete removal of
the organ leads to a complex of particular symptoms that
we today have learned to associate with lack of thyroid
hormone. Kocher reversed these symptoms by
implanting thyroid tissue to these patients and
1 performed the first organ transplant
1  In the following years, Kocher and other surgeons used
2 thyroid transplantation to treat thyroid deficiency that
2 had appeared spontaneously, without a preceding organ
removal.
2
 Thyroid transplantation became the model for a whole new
2
therapeutic strategy, organ transplantation.
 By 1900, the idea that one can successfully treat internal
2 diseases by replacing a failed organ through transplantation
2 had been generally accepted.
3  Pioneering work in the surgical technique of transplantation
3 by the French surgeon Alexis Carrel, with Charles Guthrie,
3 with the transplantations of arteries or veins
 Their skillful anastomosis operations, the new suturing
4 techniques, laid the ground work for later transplant
4 surgery and won Carrel the Nobel Prize in Physiology or
5 Medicine
 From 1902, Carrel performed transplant experiments on
dogs. Surgically successful in moving kidneys, hearts, and
spleens. He was one of the first to identify the problem
of rejection which remained insurmountable for decades.
 The strategies of matching donor and recipient and the use
of different agents for immune suppression did not result in
substantial improvement so that organ transplantation was
largely abandoned after WWI
 Major steps in skin transplantation occurred during the
WWI, notably in the work of Harold Gillies at Aldershot.
Among his advances was the tubed pedicle graft.
TERMINOLOGY
TRANSPLANTATION
 Transferring of one organ, tissue or cell to another site in
same person of another person
 Moving of an organ from one body to another, or from a
donor site to another location on the patient’s own body, for
the purpose of replacing the recipient’s damaged or absent
organ
IMPLANTATION
 Placing or firmly securing an organ, tissue, cells, or devices
into the body.
 Examples:
o Implantation of fertilized ovum
o Silicon implant
o Hip prosthesis in hip
o Knee replacement
GRAFT
 Organ or tissue transferred
 Types:
o Auto graft
 transplant from one body to the same body
o Allograft
 transplant from one body to another body of the
same species
o Xenograft
 transplantation between two different species
Page 1 of 5
 Organ Transplantation & Immunology

o Orthotopic graft  Most organs are generally better for donation

 transplantation of tissue to its normal anatomic
position
 placed to the same site from where it was removed
o Heterotopic graft
 transplantation of tissue or organ into a position it
normal does not occupy
 placed to a site different from where it was taken
THE RECIPIENT
 Patient – the patient to receive the donor organ or tissue
 Site – the place where the organ can be implanted
compared to organs derived from cardiac-death
donors
DONORS AFTER CARDIAC DEATH
 Organs derived from these donors generally have inferior
outcomes when transplanted.
 Organs harvested should be transplanted AT ONCE!
 Tissues may be recovered from donors up to 24 hours
after cessation of heart beat  maybe stored in banks
MAJOR ORGAN TRANSPLANTATIONS

CRITERIA FOR PATIENT TO RECEOVE THE TRANSPLANT THORACIC ORGANS

ORGAN Heart Deceased-donor only
 End stage disease of the organ, no other organ replacement Lung Deceased-donor & Living related donor
 For paired organs: both organs are diseased OR a single Heart/ Lung Deceased-donor, Domino transplant
organ is diseased and no longer able fully to function, ABDOMINAL ORGANS
endangering the life of the patient Kidneys Deceased-donor & Living donor
 No other possible options Liver Deceased-donor & Living donor
o End-stage renal disease (option of dialysis indefinitely) Pancreas Deceased-donor only
o Choice: indefinite dialysis, or organ transplantation
Intestine Deceased-donor & Living donor
Frequently, patients are not in the best of health when they
Stomach Deceased-donor only
receive the organs and needs intensive care management.
TISSUES, CELLS, FLUIDS
Hand Deceased-donor only
THE DONOR
Cornea Deceased-donor only
 Patients who will donate the organs
Skin
Face replant Autograft
TYPES OF DONORS Face transplant Allograft
Islets of
LIVING DONORS Deceased-donor only
Langerhans
 Remains alive and donate renewable cells of tissue (e.g., Bone marrow Living donor & Autograft
blood), or donate organ or part of an organ in which the Blood
remaining organ can regenerate or take on the workload of Living donor & Autograft
transfusion
the rest of the organ Blood vessels Deceased-donor & Autograft
 Primarily, single kidney donation Deceased-donor &
 Partial liver donation, lung lobe donation Heart valve
Xenograft (porcine/bovine)
 Types of living donors Bone Deceased-donor & Living donor
o Living Related Donors – siblings, twins, parents
o Living Non-related Donors
INDICATIONS OF ORGAN TRANSPLANTATION
 When patient has end-stage organ failures
DECEASED DONORS  No other options/options exhausted
 Organs from brain-dead donors (recognition of brain death  By choice: indefinite dialysis vs transplantation
as criteria)
 Organs from donors after cardiac death (circulatory CRITERIA FOR ORGAN DONATION
death), Non Heart-beating donors, Cadaveric donors
 Brain death (Better!)
 Cardiac death
EVALUATION OF LIVING DONORS
Objectives: BRAIN DEATH
 Anticipation of how patient functions after donation
 Diagnosis is based on clinical examination & diagnostic tests
 Evaluation of how much can be donated
 The physician should demonstrate the following:
 Evaluation of the function of the remaining organ
o Correction of potentially reversible causes of coma:
(functional reserve) after partial donation of unpaired organ
 Hypothermia, sedating medications, metabolic
(e.g., liver), or single organ of paired organs (e.g., kidneys)
disturbances
o Evaluate the remaining kidney before removing the
 Endocrine disturbances, hypoxia of hypercarbia
donor kidney
o Absence of brainstem reflexes:
o Evaluate the remaining function of remaining liver lobe
 Cornea
 Pupillary reflexes
TYPES OF DECEASED DONORS  Oculovestibular
 Gag
BRAIN-DEAD DONORS  Oculocephalic
 Brain-dead donors have to be kept alive by ventilators and o Lack of respiratory effort (apnea test) with pCO2 rise to
or drugs and maintain organ viability prior to removal. >50-60mmHg

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 Organ Transplantation & Immunology

o Confirmatory EEG, isotopic flow study, transcranial MANAGEMENT OF DONORS

Doppler; repeated after 2-24 hour interval to eliminate
observer error and show persistence of clinical state
PATIENT MONITORING
 Lines
EVALUATION OF POTENTIAL DONORS o Central venous and radial artery lines
o Pulmonary arterial catheters (often)
GENERAL SCREENING  Vitals (Monitor hourly or more frequently as needed)
 Basic laboratory values: o Blood pressure
o CBC o Pulse pressure
o Electrolytes o Central venous pressure (CVP)
o Glucose o Pulse oximetry
o Arterial blood gas  Temperature
 ABO blood typing o Monitor every 2 hours and use cooling or warming
 HLA typing blankets to maintain temperature at 97-100°F
 Blood cultures
 Sputum Gram stain, culture and sensitivities BLOOD PRESSURE AND VENT MANAGEMENT
 Urinalysis, culture and sensitivities: (RULE OF 100s)
o HIV  Maintain systolic blood pressure greater than 100mmHg
o Epstein-Barr virus (EBV) with minimal inotropic support (e.g. dopamine,
o Cytomegalovirus (CMV) neosynephrine, Levophed)
o Human T-cell leukemia virus type 1 (HTLV-1)  Ensure the urine output is at least 100-300cc/h
o Hepatitis B & C virus serology  Ensure that pO2 is at least 100mmHg on the least amount
 Venereal disease research laboratory (VDRL) test or rapid of fraction of inspired oxygen (FiO2).
plasma reagent (RPR) test
 Inguinal lymph nodes tested for evaluation of recipient
FLUID BALANCE
sensitivity
 Adjust intravenous (IV) fluid to maintain CVP of 4-12
mmHg and urine output of 1-3 cc/kg/h
SCREENING FOR THE HEART
 Treat diabetes insipidus (DI):
 ECG, Chest X-ray
o Suspect DI if urine output is greater than 3cc/kg/h with
 Echocardiogram
urinary specific gravity of < 1.005.
 Cardiac catheterization (male>40, female >45)
o Treat with DDAVP or vasopressin. Do not administer
 Creatinine kinase (CK), isoenzyme of CK with muscle and
within 4 hours of procurement
brain subunits (CK-MB), troponin levels
 Maintain CVP at 4-12mmHg as tolerated by patient
hemodynamic
SCREENING FOR LUNG DONORS
 Chest X-ray MISCELLANEOUS
 Bronchoscopy
 Electrolytes
 ABG on 100% fraction of inspired oxygen (FiO2), then serial
o Correct electrolyte abnormalities as observed
ABGs
o Elevated sodium is associated with adverse outcomes in
liver transplantation
SCREENING FOR PANCREAS DONORS  Steroids
 Serial blood glucose o Administer 15-30mg/kg Solu-Medrol every 8-12hours;
 Amylase and lipase level this has been shown to increase the number of organs
transplanted from each donor
SCREENING FOR KIDNEY DONORS  The role of thyroxine replacement in donor management is
 Electrolytes controversial; consider this in cases of refractory
 BUN, Creatinine hypotension, arrhythmia, or cardiac dysfunction. Donor
thyroid replacement has been shown to reduce 30-day
SCREENING FOR LIVER DONORS mortality in heart transplant recipients.
 Liver function tests (LFTs)  Correct coagulopathy and transfuse blood to hematocrit
 Liver biopsy for donors with: (hct) of 30 or greater
o BMI >32  Administer empiric cefazolin or equivalent
o >72 years old (60 years old if with DM)
o Past liver disease ORGAN PROCUREMENT
o Alcohol abuse  Protection and Preservation of donor organs
o Fatty liver disease  Ischemic time: warm and cold
o Confirm hepatitis serologies
 Prothrombin time PREPARATIONS
 aPTT  Coordination of several surgical teams from institutions
 Coordination of teams operating on the recipient and
donors (example ni sir: Dapat daw ready na at naka-bukas
na ang abdomen ng recipient ng organ. Hindi yung kung
kelan dumating saka pa lang bubuksan.)
 Adequate volume resuscitation of donors (Brain edema
leads to DI  hypovolemia state)

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STEPS IN ORGAN PROCUREMENT (HARVEST)
 An incision from the suprasternal notch to the pubis is
made
 Chest is opened via media sternotomy and the abdominal
cavity is entered
 Thoracic and abdominal cavities are examined by respectibe
teams for evidence of occult pathology and gross suitability
of organs for transplant
 The small bowel is retracted, right colon is mobilized, the
posterior peritoneum is incised, and the duodenum and
pancreas are reflected allowing exposure of the Inferior
Vena Cava (IVC) and aorta
 Attachments of the heart, lung, liver, kidneys and pancreas
are incised; the organs are readied for removal
 The aortic arch, IVC, abdominal aorta, and portal vein or
tributaries are cannulated for infusion of the preservative
solution
 The aortic arch and supraceliac abdominal aorta are cross-
clamped. A cold preservative solution is infused through the
inferior aortic, portal, and cardiac cannulae, with drainage
of effluent via the IVC.
 The thoracic and abdominal cavities are packed with ice
 The organs are removed to the back table for initial
preparation and packaging for transport (Parang
namalengke lang daw. LOL!)
IMMUNOLOGY IN ORGAN TRANSPLANTATION
 The immune system remains the most formidable barrier to
transplantation as a routine medical treatment
 The immune system has developed elaborate and effective
mechanisms to combat foreign agents including
transplanted organs which are recognized as foreign by the
recipient’s immune system
 The antigens responsible for rejection of genetically
disparate tissues are called histocompatibility antigens.
They are products of the histocompatibility genes
 Histocompatibility antigens are encoded on more than 40
loci, but the loci responsible for the most vigorous allograft
rejection reactions are located on the major
histocompatibility complex (MHC)
 In humans the MHC is called the human leukocyte
antigen (HLA) system and is located on the short arm
of chromosome 6, near the complement genes. Other
antigens cause only weaker reactions but combinations of
several minor antigens can elicit strong rejection responses
 The MHC are co-dominantly expressed which means that
each individual expresses these genes from both the alleles
on the cell surface. Furthermore, they are inherited as
haplotypes or 2 half sets (one from each parent).
o Hence a person is half identical to each of his or her
parents with respect to the MHC complex
o 25% chance that an individual might have a sibling who
is HLA identical
 The MCH molecules presents antigenic peptides to T cells
since the T lymphocytes only recognize antigen when
presented in a complex with an MHC molecule
 There are 2 MHC classes
o The class I molecules are normally expressed on all
nucleated cells. These molecules are responsible for the
presenting antigenic peptides from within the cell (eg,
antigens from the intracellular viruses, tumor antigens,
self-antigens) to CD8 T cells
o The class II molecules are present on extracellular
antigens such as extracellular bacteria to CD4 T cells.
They are expressed only on the professional antigen-
presenting cells (APCs), such as dendritic cells, activated
macrophages, and B cells
Agatep. Detera. Doong. Rodriguez. Tejano. Villacorta
Organ Transplantation & Immunology
REJECTION
MECHANISM OF REJECTION
 The immune response to a transplanted organ consists of
both cellular (lymphocyte mediated) and humoral (antibody
mediated) mechanisms
 Although other cell types are also involved, the T cells are
central in the rejection of grafts
 The rejection reaction consists of the sensitization and the
effector stage
 SENSITIZATION STAGE
o In this stage the CD4 and CD8 T cells via their T cell
receptors recognize the alloantigen expressed on the
cells of the foreign graft
 EFFECTOR STAGE
o Alloantigen-dependent and independent factors
contribute to the effector mechanisms
o Initially, non-immunologic “injury responses” (ischemia)
induce a nonspecific inflammatory response
o Expression of adhesion molecules, class II MHC,
chemokines and cytokines is upregulated
o Antigen presentation to T cells is increased. Shedding of
intact soluble MHC molecules
o Activation of the indirect allorecognition pathway
o CD4-positive T cells initiate macrophage-mediated
delayed type of hypersensitivity (DTH) responses and
provide help to B cells
o Endothelial cells activated by T cell derived cytokines
and macrophage express class II MHC, adhesion
molecules, and co-stimulatory molecules
o Presents antigen
o Recruit more T cells  amplifying the rejection process.
CD8 positive T cells mediate cell-mediated cytotoxicity
reactions inducing apoptosis
 MEDIATORS OF REJECTION
o Various T cells and T cell-derived cytokines such as IL-2
and IFN-γ are upregulated early after transplantation.
Later, β-chemokines like RANTES (regulated upon
activation, normal T cell expressed and secreted, IP-10
and MCP-1 are expressed
 promoting intense macrophage infiltration of the
allograft
o IL-6, TNF-a, inducible nitric oxide synthase (iNOS) and
growth factors also play a role in this process. The
growth factors including TGF-β and endothelin
 cause smooth muscle proliferation, intimal
thickening, interstitial fibrosis and, in the case of the
kidney, glomerulosclerosis
 The final common pathway for the cytolytic process is
triggering of apoptosis in the target cell
After activation of CTLs
Form cytotoxic granules that contain perforin and
granzymes
These granules fuse with effector cell membrane and
extrude the content into the immunological synapse
The granzymes are inserted into the target cell cytoplasm
Granzyme B causes direct cleavage of procaspase-3 and
indirect activation of procaspase 9
Trigger rejection apoptosis. (this has been shown to play
dominant role in apoptosis induction in allograft)
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 Organ Transplantation & Immunology

CLINICAL TYPES OF REJECTION 2. ACUTE HUMORAL REJECTION

HYPERACUTE REJECTIONS
 Most rapid and aggressive form of transplant rejection
mediated by pre-existing circulating antibodies against the
graft
 Example: Anti-ABO antibodies responsible for the
transfusion reaction when patients receive an ABO-
mismatched blood transfusion
o Anti-ABO antibodies are capable of causing hyperacute
rejection of ABO-mismatched organ transplants and the
latter pose a major hurdle for the use of animal tissues
for transplantation
 How organs are damaged:

CHRONIC REJECTION
 Fewer chronic rejection as cause of major cause of graft
loss
 Benefited little from recent advances in immunosuppression
 Usually develops slowly & insidiously over months & years
 Characterized by a progressive decline in graft function
 Primary cause: most likely due to an antigraft immune
response, as supported by:
o development of chronic rejection is strongly associated
with previous episodes of acute rejection
o with the degree of HLA mismatch
 Risk factor:
1. Ischemia/reperfusion injury
o All of which are initiated within minutes of re-
2. Immunosuppressive drug toxicity
establishing the blood supply to the transplant
3. Hyperlipidemia
4. Infection
ACUTE REJECTIONS (HUMORAL OR CELLULAR)  Diagnosis:
 Result of the immune system recognizing new, foreign o Thickened arterial intima d/t edema and infiltration
antigens and involves both humoral and cellular throughout the organs
components o Classic hallmark: smooth muscle cell proliferation in
 Most likely to happen within the first few weeks after the medial layer
transplantation but may be triggers at a much later stage,  Leads to:
most likely by infection or reduction 1. partial or complete obliteration of vessel lumen
2. disrupted elastic lamina
CHARACTERISTIC FEATURES 3. proliferation

1. ACUTE CELLULAR REJECTION IMMUNOSUPPRESSION IN TRANSPLANTATION

 Targets or destroys graft endothelial cells
 Experimental immunosuppressive agents demonstrated that
acute rejection could be prevented
 Azathioprine and steroids were the standard form of
immunosuppressive treatment until late 70s
 Cyclosporine, alongside azathioprine and steroids, then
became the treatment of choice for the next 20 years
o permitted the successful introduction of heart and liver
transplantation program
 Treatment is tailored to individual needs

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