IMMUNOLOGY AND ORGAN TRANSPLANTATION MODERN TRANSPLANTATION BIOLOGY

LECTURER: WILFREDO T. POLIDO JR., MD Freemartin Cattle

TRANSPLANTATION - Non-identical cattle twins who shared a placenta in utero chimeric for red
Transplantation is the process of taking a graft cells, tissues or organ from blood cells which carry the genetic makeup of the non-identical twins
one individual (donor) and placing it into another individual (recipient/host). - Skin grafts were exchanged between these twins, they did not undergo
🎙 Autologous blood transfusion — same individual; transfusion of your blood to yourself rejection which is a phenomenon called T-cell ignorance
🎙 Because they have been pre-exposed during their younger years or when the immune
system is still maturing, they thought that the antigen from the other individual is part of
TYPES OF TRANSPLANTATION
their own cell. After birth, when transplant/grafting was done, they did not develop rejection
As to location:
Medawar concluded:

1. Orthotopic Transplantation
☞Antigen delivered to the immature individual during intrauterine
− normal anatomic position (e.g. Heart, Liver, and Cornea) development or shortly after birth would result in long-term immunological
tolerance
☞The concept of inducing stable tolerance to prospective recipients of organ
transplant is still the main focus of transplantation research today
☞Main focus of gene therapy and gene manipulation (still experimental)
OVERVIEW OF IMMUNOLOGY

IMMUNITY is a biological phenomenon, which consists, in long term

🎙 In patients with heart failure, you want the blood pressure in the circulation to be autosupport, of the genetic ‘self’ and ‘non-self’ balance in the body under foreign
restored, it requires attaching of the heart to the great vessel which is the normal anatomic
position surroundings
2. Heterotopic Transplantation
- Immune System develops and releases certain mechanisms to exert this
− non-anatomic position (e.g. Kidney and Pancreas) phenomenon
- Role of thymus gland in immune tolerance to self-MHC Ag gave the basis
for gene therapy
☞Paralysis of certain components of immunity may lead to immunodeficiency
and loss of host defense
☞Dysregulation of the immune system may result in autoimmune disease,
allergies (based on hypersensitivity of four types) and tumors
Function:
- Defense from ‘non-self’
- Elimination of modified ‘self’
🎙 In general, the native kidney is not removed since it has already shrunken, the kidney - Regulation of cell/tissue growth and maturation
transplanted will be put on top of the two kidneys EXCEPT in patients with related diseases
leading to infection 🎙 There are certain immunosuppressant medications which carry risk of
(e.g. patients with kidney stones —remove kidneys because of possible infection; since developing cancer in long term use. Certain medication also has high association
the patient will be receiving immunosuppressants, it prevent rejection but will also suppress with post-transplant lymphoproliferative disease (benign to malignant forms of
other functions of the immune system/defenses against infection) hyperactivity of lymphoid cells)
🎙 Pancreas — placed in the iliac fossa
INNATE MECHANISMS/NON-SPECIFIC RESISTANCE

As to genetic relationship:
The elements of the non-specific (innate) immune system include:
1. Syngeneic (Isograft)
☞Anatomical barriers

− genetically identical strain; − Skin, intestinal movement, oscillation of broncho-pulmonary cilia

− involved identical twin ☞Secretory molecules

2. Allogeneic (Allograft or Homograft) − Organic acids in skin secretions, thiocyanate in saliva, bile acids and low
− genetically different members of the same species; molecular weight fatty acid in lower GIT
− most common form of transplant − Other secretory molecules
3. Xenogeneic (Heterologous, Heterograft or Xenograft) a. Transferrin and Lactoferrin – deprive organisms of iron
− among different species; b. Interferon – inhibits viral replication & activates immune cells
− e.g. heart valves—harvested from porcine tissue c. Lysozyme (serum/tears) – destroy cell wall (peptidoglycan)
4. Autotransplant (Autograft, autologous)
d.Fibronectin – opsonize bacteria and promote phagocytosis
− within the same individual e. Complements – aid destruction of microorganism
HISTORICAL BACKGROUND
f. Acute phase proteins (such as CRP) - interact with complement system
Although attempts at a transplant date back to ancient times, the impetus for proteins
modern transplantation was World War II and the Battle of Britain g.TNF alpha – suppress viral replication and activates phagocytosis
🎙 Severe burn injuries improve with skin grafting. The skin graft still fail even with the 🎙 Although they are non-specific, they are involved in inflammatory reactions that may
control of infection. They recognized that it is linked to T-cells/WBC, which is not entirely also stimulate T-cell responses leading to as specific immunologic response.
related to infection in the surgical site. ☞Cellular components

− Phagocytic cells (Neutrophils/PMNs, Macrophages, Monocytes) — most

“The failure of a skin graft to ‘take’ was the result of a process termed important cellular components of the non-specific immune system
immunologic rejection, which was mediated by the recipient’s white blood cells” — − Other Cells — Natural killer (NK), Killer (K), Lymphokine activated killer
Sir Peter Medawar
 (LAK) cells, Eosinophils
🎙 Non-specific, intermediary to specific immune response by becoming an ANTIGEN
PRESENTING CELLS. When antigens interact, the phagocytes engulf them and these
phagocytes also serve as APC. They interacting with T-cells, recognizing it as non-self.

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 ADAPTIVE IMMUNITY
Immune Response
☞A response to specific immune stimulus (antigen) that involves cells of the Innate Immunity Adaptive Immunity
immune system and frequently leads to a state of immune memory Response is antigen dependent Response is antigen dependent
☞Occurs after a lag period during which immune B and T cells become
activated There is immediate maximal response There is a lag time between exposure
and maximal response
🎙 Activation of the proliferation of these cells only to specific cells with immunologic Not antigen specific Antigen Specific
memory. (e.g. if vaccinated with Hepa B and exposed to HBV, the body will stimulate
proliferation of the T-cells which contain defenses specific against hepatitis B) Exposure does not result in Exposure results in immunologic
immunologic memory memory
☞Specific recognition and selective elimination
of foreign molecules Types of Adaptive Immunity 🎙 Adaptive immunity — concept utilized in giving inactivated live vaccines
Active - reaction of your own
☞Involves specificity, diversity, memory and self/ system (exposure to antigen) TRANSPLANTATION IMMUNOLOGY

non-self recognition Passive - borrow immune ☞ Transplantation of almost any type of vital organ or tissue is an effective
agents from another person
Specificity
therapeutic modality
☞can distinguish subtle differences in molecules ☞Most transplants are done from genetically different donors
☞e.g. pig and human insulin are different in only very slight ways − Consider immunological response of the recipient to the transplantation
− Yet some diabetics have allergic reactions or immune responses to pig antigens presented by the donor graft
insulin
Diversity
1. Exposure of a recipient to different histocompatibility antigens
− can recognize literally billions of different structures on foreign molecules (transplantation antigens)⟶Transplant Immunity
🎙 Several proteins in a foreign molecule can serve as a stimulus for reaction of the 2. Success of any organ transplantation⟶Control of the immune system to
immune system, processed and recognized by immune system as different from own allow adaptation of transplanted organ⟶Prevent transplant rejection
protein
TRANSPLANTATION: HISTOCOMPATIBILITY ANTIGENS

Memory

☞one of the greatest attributes of the immune system

- dictate the compatibility of the organ being transplanted
HLA (Human leukocyte antigens):

− Very important once the body has mounted an immune response to a

- MHC antigens of man (first detected on leukocytes) cause the strongest
particular molecule and rid the body of that molecule
immune response and are important in rejection
− The second time it is exposed, it reacts with a heightened state of activity
- Located on chromosome 6
which proceeds quickly and effectively eliminates the offending molecule
- Enable the immune system to recognize both self and foreign antigens
Self/non-self recognition

☞Ability to recognizes foreign molecules from those of its own body (mainly Major Classes of MHC

☞Class I
function of T-cell) Class I and Class II antigens are expressed
☞Class II on cells and tissues; important in transplant
− It has major consequences for organ transplantation
☞Class III
− Even with slightest breakdown it can still cause debilitating or fatal
- Antigens are represented on proteins in serum and other body fluids
autoimmune response
- Have no role in graft rejection
Full T-cell activation leading to cytokine expression and clonal expansion
MHC genes

requires:
☞Favorable local environment (tissue injury)
1. Class I HLA

− Are found on virtually all cell surfaces

🎙 Monitor rejection to prevent full activation of T-cell
• Bind foreign protein antigens including transplanted tissues
☞External signals to T-cell

− Are bound by antigen specific T-cells

− Signal 1 antigen presentation by APC
• Recognized by cytotoxic T cells
− Signal 2 costimulation by APC (B7 molecule)
2. Class II HLA

• CD28 positive signal: stimulate proliferation

− HLA-DR, HLA-DP, and HLADQ
• Cytotoxic T-lymphocyte (CTLA4) negative signal: no need to replicate
− found only on antigen presenting cells (B lymphocytes, macrophages, and
− Signal 3 growth-promoting cytokines from activated T-cells
dendritic cells of lymphoid organs)
• TH1-like (IFN and IL2) or TH2-like (IL4, IL5, IL6, etc)
− Play the most predominant role in the initial immune response to foreign
🎙 After stimulation, there will be a positive signal releasing cytokine which stimulate
replication of T-cell transplantation antigens
☞Cytotoxic T-Lymphocyte Antigen 4
− Foreign antigens activated CD4+ T-cells undergo clonal expansion by the
☞T-Cell Receptor molecule
regulatory cytokines, interleukin-2 (IL-2)
☞CD 28 (Cluster of Differentiation 28)
Laws of Transplantation

1. Immunocompetent host recognizes the foreign antigens. It can mount an

🎙 APC with MCH presented to TCR. If it is recognized as non-self, it will interact with CD28
molecule which will release a positive signal leading to T-cell activation. After T-cell
activation, it will stimulate T-cell to release IL-2 which will attach to IL-2R to stimulate T-cell to
proliferate.
immune response against the organ ⟶Rejection (Host Versus Graft
rejection)
2. Immunocompromised host grafted with foreign immunocompetent
lymphoid cells, immunoreactive T-cells in the graft recognize the foreign
antigens on the host tissue⟶Damage of the host tissue (GVH)
🎙 It is important to maintain the balance in how much immunosuppressants to give. If too
much=immunocompromised host

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 HOST-VERSUS-GRAFT REACTION
Chronic GVH reactions

☞Allograft rejection
☞Time of rejection depends on the antigenic disparity between the donors
and the recipient
🎙 The more similar they are, the less likely they will reject —longer survival of the organ in
the recipient
☞Duration of graft survival follows the order, xeno < allo < iso = autograft
☞MHC antigens are the major contributors in rejection, but the minor
histocompatibility antigens also play a role
☞Rejection due to disparity in several minor histocompatibility antigens may
Hyperpigmented lichenoid papules Buccal erosions and exophytic masses
be as quick or quicker than rejection mediated by a MHC antigen and toxic epidermal necrosis like over the tongue
appearance
🎙 Profile the patient if immunocompromised or not; e.g. A patient who has kidney failure
with uncontrolled diabetes, px may sometimes suffer from anemia bc of decrease EPO as a CLINICAL REJECTION

result of contracted kidneys. Many px might have received blood transfusions in the past Allograft Rejection

before KF that require kidney transplant. During the time of transplantation, the patient ☞Major obstacle in organ transplantation
might contain several antibodies against protein molecules from different individuals which
have donated blood previously. The risk of minor reaction might be higher in these patients. ☞Reaction of the host against allo-antigens of the graft (HVG) results in its
There are certain situation where you don't only consider screening for major rejection
histocompatibility antigens but also screen fro minor mismatches.
☞Most importantly, graft dysfunction is observed
GRAFT-VERSUS-HOST (GVH) REACTION
− Screen for the transplanted organ (if kidney transplant, request for
☞H i s t o c o m p a t i b l e l y m p h o i d c e l l s , w h e n i n j e c t e d i n t o a n
creatinine. If liver, request lover enzymes)
immunocompromised host, are readily accepted Warning signs: fever, flulike symptoms, hypertension, edema or sudden weight
☞BUT, the immunocompetent T lymphocytes among the grafted cells
gain, changes in heart rate, shortness of breath, and pain over graft site
recognize the alloantigens and, in response they proliferate and
Type of Organ Warning Signs of Rejection
progressively cause damage to the host tissues and cells Transplantation
Common Clinical manifestations of GVH rejection
- Pain or tenderness over the transplant site
☞Diarrhea, erythema, weight loss, malaise, fever, joint pains, - Fever
- Flue-like synpltoms: chills, nausea, vomiting, tiredness,
etc⟶Ultimately death Kidney, kidney/ headache, dizziness, body aches and pains
Acute Rejection
pancreas - Deacreased urine output
☞Occur within 100 days
- Sudden weight gain or swollen feet or ankles
- High blood pressure
☞Staging based on skin involvement
- Fever
☞Stage 1: 25% - Shortness of breath
☞Stage 2: 50% - Flu-like symptoms
Heart - Difficulty sleeping on your back
☞Advance stage: 100% or bullae - Abnormal or irregular heartbeat
☞Treatment - Weight gain or swelling
- Decrease in blood pressure
− Methotrexate
− Anti T-lymphocyte - Yellow skin of eyes
- Itching
− 50-75% respond to steroid alone Liver - Tea-colored urine or light-colored stool
☞Mortality generally from sepsis - Weight gain or swelling of the legs or stomach
- Sudden tiredness
Acute GVH reactions
- Unexplained shortness of breath
- Chest pain
Lung
- Dry cough
- General ill feeling
- Decreased amount of air inhaled and decreased speed
of air flow during a breath
- Fever
- Diarrhea or change in stool patterns
- Abdominal distention or pin
Intestine - Flu-like symptoms

- Weight loss, poor appetite
- Bloody stools
Graft-versus-host (GVH) Reaction
Acute GVHD Chronic GVHD Hyperacute Rejection

☞Specific preformed antibodies of the recipient to an antigen expressed by

Onset ≤100* days after transplant >100* days after transplant
the donor.
Acute GVHD
Recepient age ☞The recipient has high preformed antibody titer
Risk Recipient age Female-to-male sex mismatch
factors ☞Signs of rejection within minutes to hours
(male recipient receiving from
female, the risk is higher) − Due to immediate reaction of antibodies and complement
Skin Multisystem: skin, liver. GIT. eyes, ☞ABO and HLA mismatch
Target Liver BM, immune system, mucus
organs 🎙 There are situations wherein ABO mismatch transplant may be done such as in liver
GI Tract membranes transplant.
Prophylaxis —Methotrexate Prophylaxis — anti-infective ☞Exposure may also be in the form of transfusion or pregnancy
Prophylaxis — anti infective Corticosteroids
Treatment Coticosteroids ☞Though hyperacute rejection is untreatable, it is mostly a preventable
Supportive care Supportive care
phenomenon
*Mode; acute GVHD may occur as early as 7-10 days; classical onset of chronic ☞Can be prevented by detecting the antibody with simple cross-matching
GVHD is 50-70 days but may be greater than 12 months prior to transplantation
− Lymphocytotoxic cross-match and ABO typing

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 ☞Complement-mediated lysis induces a procoagulant state (platelet Type Onset Cause
activation, etc)⟶Immediate graft thrombosis Hyperacute Minutes to hours Preformed anti-bodies
Vascular Rejection
Accelerated Days Reactivation of sensitized T-cells
☞A delayed variant of Hyperacute Rejection Acute Days to weeks Primary activation of T-cells
☞Offending antibodies exist in circulation at levels undetectable by the cross- Chronic Months to years Unclear
match assay Procedures to Enhance Graft Survival

☞Initial graft function, followed by deterioration on or about postoperative ☞Most successful transplantation programs have been with kidneys, corneas
day 3 and liver
Accelerated Rejection (2nd set; Secondary)
☞Success has been due to a better understanding
☞Transplantation of a second graft, shares a significant number of antigenic − Immunological mechanisms
determinants with the first one − Definitions of MHC antigens
☞Rapid (2-5 days) rejection − Development of more effective immunosuppressive agents
☞It is due to presence of T-lymphocytes sensitized during the first graft − Improved technique of doing the transplant
rejection (prior exposure) Factors Influencing Rejection

☞Immediate production of lymphokines, activation of monocytes and ☞Cold ischemia time

macrophages, and induction of cytotoxic lymphocytes 🎙 Organ preservation: up-to 24hrs; longer cold preservation, the higher the risk of
Acute Rejection (1st set; Primary)
rejection most likely because of the decay of proteins in the organ which is immunologically
☞Normal reaction that follows the first grafting of a foreign transplant stimulating to the T-cells
☞Takes days – weeks ☞Donor age
☞Most common form ☞CMV infection
☞Occurs most frequently in the first 6 months after transplantation ☞Histocompatibility
☞Mediated by T-lymphocytes sensitized to class I and class II antigens of ☞Hyperlipidemia
allograft, production of lymphokines and activation of monocytes and ☞Hypertension
macrophages ☞Diabetes mellitus
☞Immunosuppressive drugs are most effective in preventing this type of Donor Selection

rejection ☞MHC identity with the recipient

☞Monitoring for acute rejection must be intense, particularly during the first − An identical twin is the ideal donor
year after transplantation − Grafts from an HLA matched sibling have 95-100% chance of success
− diagnosis based on biopsies of transplanted organ, special immunologic ☞For optimal graft outcome compatibility at 3 HLA Loci (HLA-A, HLA-B, and
stains, and laboratory tests (elevated creatinine—kidney; elevated liver HLA-DR) is most desirable
enzymes—liver; elevated glucose, amylase, lipase—pancreas) ☞One haplotype-identical parent or sibling must match at the HLA-D region
☞Unexplained graft dysfunction would require prompt biopsy ☞An ABO compatibility is essential
− Evaluation for the lymphocytic infiltration and graft parenchymal Recipient Preparation

necrosis characteristic of acute rejection ☞Infection free

☞Treatment leads to successful restoration of graft function in 90 to 95 ☞Cancer screening
percent of cases ☞Optimal cardiac function
☞Pulse steroid is the main treatment (prednisone) ☞Current Diseases is not active
☞Failure to treat results almost uniformly in graft loss 🎙 In cases of hepa B, give patient anti-hepa treatment before undergoing transplant
☞Prompt recognition of acute rejection is imperative (ideally).

Chronic Rejection
☞Immunosuppression
☞Grafts may survive for months or even years − Induction and maintenance of immunosuppressants
☞Suddenly exhibit symptoms of rejection
☞Mechanism of which is not entirely clear
− Cytokines from lymphocytes or macrophages, growth factors and
eicosanoids and PAFs
− Perivascular inflammation
☞Biopsy: Progressive intimal hypertrophy of the small to medium-sized
arteries that in turn leads to interstitial fibrosis. Atrophy and eventual failure
of the organ transplanted
☞Develops as early as 6 to 12 months after transplantation
☞No standard treatment for chronic rejection
− Modify maintenance immunosuppression
Patterns of Rejection

IMMUNOSUPPRESSION

☞Most essential part of allo-transplantation

☞Most common family of agents
− Cyclosporin A, FK 506(calcineurin inhibitor)
− Rapamune (IL-2)
− Prednisone, Hydrocortisone (Cortocosteroid)
− Basiliximab, Daclizumab (immunomodulator)
− OKT3
− SGN 40
− CTLA4 Immunoglobulin (NOT antibody)
− Antimetabolite

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Cyclosporine A and FK 506(Tacrolimus)
− Useful for acute graft rejection
☞Cyclosporine is a cyclic polypeptide produced by a fungus from Norway − Convenient dosing of every 14 days
(Beauvaria nivea) − No significant risk of lymphoma
☞Tacrolimus is a macrolide antibiotic isolated from Streptomyces Anti-CD3

tsukubaensis ☞Orthoclone OKT3 (Muromonab-CD3)

☞Both inhibits IL2 synthesis following antigen receptor binding (CNI) − Murine monoclonal antibody to the CD3 antigen of human T-cells
☞Both derived from fungi − Deplete CD3 (+) T-cells after APC interaction
☞Both may affect kidney function (monitor kidney function in patients) − IgG2a antibody against all differentiated T-cell
Rapamycin
− No signal for cell proliferation
☞Interferes with signal transduction following IL2 and IL2 receptor interaction − For high-risk rejection
☞Binds with FKBP12 and TOR • Anaphylaxis

− Arrest signal for cell replication • Neurologic side effects (Cytokine release syndrome)

− Benefit cancer patients due to anti mitotic effect • Risk of Post transplant lymphoproliferative Disease (PTLD)—

− Cause thrombocytopenia and diarrhea lyymphadenopathy, lymphomas

☞Rapamune (Sirolimus) carry risk for anastomotic dehiscence and lymphoma Anti-CD40

Glucocorticoids
☞SGN 40
☞Prednisolone used in transplant since the 1950s
☞Blocks the production of IL-1 and IL-6 by antigen presenting cells
☞Most transplant patients are maintained on low doses of corticosteroids for
− Blocks B-cell differentiation as well as costimulation (signal2) of T-cells
• Anti-cancer properties
• More popularly used for lymphomas and myelomas

the life of the transplant CTLA4 Immunoglobulin

− Newer protocols are eliminating the use of corticosteroids replaced by ☞Abatacept and Belatacept
Azathioprine due to its adverse effects − stimulate CD28 receptor analog
☞Adverse effects − Higher affinity to B7 molecule
− Hypertension, hyperlipidemia, ulcer disease, diabetes, obesity, cataracts, • Blocks signal2 (down regulates clonal expansion)

osteoporosis, and susceptibility to infection Antimetabolites

Interleukin-2
☞Class of drug used for chronic immunosuppression (for maintenance)
☞Produced mainly by helper T-cells (CD4+) − Slows cell replication/Interfere with replication of DNA
☞Lesser part from cytotoxic T-cells (CD8+) ☞Inhibit de novo synthesis (IMDPH)
☞Main function is to promote T-cell division and to increase production of ☞The two major antimetabolites
other cytokines − Azathioprine
☞Biomolecular research developed ways to modulate responses − Mycophenolate mofetil
− “Immunomodulators” ☞Azathioprine ‘Imuran’
• Basiliximab, Daclizumab − Used in clinical transplantation since the early 1960s
• blocks signal 3 − Administered orally once daily
Interleukin-2 (IL-2) promotes proliferation, inhibit apoptosis and induce − Converted in the cells to 6-mercaptopurine
cytokines • Inhibits the production of adenosine monophosphate (AMP) and
☞Main in vivo function of IL-2 is to limit guanine monophosphate (GMP)
lymphoid expansion and promote • Pronounced bone marrow suppression

peripheral tolerance. ☞Mycophenolate mofetil ‘Cellcept’

☞IL-2 is important for the differentiation of
T-helper (TH)2 cells.
☞Decline in IL stimulation leads to receptor
decay that ends the proliferative phase
proliferation and activation
− Approved in 1995 by the FDA for maintenance immunosuppression for
renal transplant
− Inhibits inosine-monophosphate-dehydrogenase which blocks production
of GMP
− Steroid free protocols; steroid resistant rejections
− MMF is selective for the de novo pathway critical to lymphocytic
• Other cells are able to recover purines via a separate scavenger pathway

− Less bone marrow suppression, fewer opportunistic infection, lower acute

rejections
ORGAN TRANSPLANTATION

Anti-IL2R

☞Basiliximab (Simulect)
− A monoclonal antibody IgG1K produced by recombinant DNA technology
− It binds to and block interleukin-2 α-chain receptor (also known as CD25
antigen) on activated T-lymphocytes
− No increase incidence of lymphoma
☞Daclizumab (Zenapax)
− Monoclonal antibody for IL-2 receptor

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Based on OPTN data as of March 25, 2016 🎙 Bile duct can be anastomosed to the bile duct of the patient but intestines can also be
utilized
☞Overall survival~90% in 1 year
☞Salvage transplantation may provide 60% overall survival in 5-years
☞Specific Concerns
− Rejection issues
− Biliary complications
− Management of hepatitis
− Recurrence of tumor
KIDNEY TRANSPLANTATION
PANCREAS TRANSPLANTATION

☞Therapy of choice for nearly all patients with end stage renal disease Schwartz’s:
☞Almost any patient in peritoneal or hemodialysis ☞only definitive long-term treatment for patients with insulin-dependent DM
☞Severe damage to kidney in patients with single kidney − Restored normal glucose
☞Chronic renal failure with symptoms − Prevents or reverses progression of secondary complication of diabetes

☞Diabetic nephropathy ☞Course of DM changed with insulin discovery (1922) by Banting and Best
☞Polycystic kidney disease ☞1,400 cases done in the US anually
☞Autoimmune disease ☞75% done with kidney transplant
− SLE ☞10% are pure pancreas transplant
− IgA Nephropathy ☞Very important option for type I DM
− Scleroderma − Hyperglycemia is the most important factor influencing complication
Types of Transplants
☞Main indication is progressive complication despite medical care
☞Living-15% − Neuropathy, retinopathy, nephropathy
− Related donors: ☞Brittle DM: frequent hypoglycemia, DKA
• Parent with 1 haplotype match 30%
🎙 Heterotopic transplant — it is not placed in its native location.
• Sibling with 1 haplotype match 25% Only the pancreatic hormones are needed. Since pancreas is a whole organ, pancreatic juices
• Identical twin 20% must be addressed by draining it to the urinary bladder, or by connecting it to the intestines
(more physiologic) but higher risk of infection since intestines contain bacteria
− Unrelated Donor
• Cadaveric-85%

Survival (1 and 5years)

☞Living donor: 95% 80%

☞Cadaveric donor: 92% 70%
☞Primary graft:
− 83% overall
− 84% for no HLA mismatch
− 77% for 4 HLA mismatches
☞Secondary graft: 80% survival
− Subsequent grafts: 79%
LIVER TRANSPLANTATION
Urinary Bladder Drainage Small Bowel Drainage
☞Treatment of choice for end-stage liver disease
☞Rejection monitoring - monitor function of pancreas
− Severe ascites, variceal bleeding, peritonitis
− Amylase, lipase, creatinin
− Episodes of encephalopathy
🎙 Screening: Blood glucose and creatinine since most of pancreatic transplantation(75%)
☞Treatment of liver cancer which due to liver cirrhosis or nature of tumor are
are performed together with kidney transplantation.
no longer amenable to other treatment options Rejection is mostly systemic phenomenon, rejection of kidney transplanted will also cause
− Should have no extrahepatic disease rejection of the transplanted pancreas.
☞Complications
🎙 If px has liver tumor and liver cirrhosis, must remove the lesion as well as the tumor (so
buong liver daw tanggalin) then liver is transplanted. − Thrombosis
🎙 If patient has lung metastasis, no point in doing liver trasplant because once − Bleeding
immunosuppresant is given, the metastasis will aggressively proliferate − Pancreatitis
☞Larger organs evoke better immune tolerance − Urologic (hematuria, acidosis, calculi, leak) —if anastomosed to the bladder
− Multiple organ transplants − Infection
− Less immunosuppressive requirement ISLET-CELL TRANSPLANTATION

− Better rejection rates than kidney transplant ☞Only the endocrine component is vital
☞Role of HLA typing ☞Whole organ transplantation
☞Principles are greatly based on the liver’s capacity to regenerate − Significant morbidity
− living donor liver transplant because when you remove part of the liver, it − Risk of major surgery
can regenerate. ☞Offers advantages similar to whole pancreas transplant
− Engrafted to liver as out-patient
🎙 inject it to the liver, islet cell will implant and grow there, producing insulin
☞Isolating islet cells is complicated
☞Major disadvantage is immunosuppression
− Limited its use to kidney patients

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 SMALL BOWEL TRANSPLANTATION
☞Early rejection episodes are strongly correlated with degree of HLA
☞ Very crucial in digestion and absorption of food incompatibility
☞At least 180cm (>25%) of the 600cm average length needed ☞Increased cold-ischemia time of graft (particularly if >48hours)
☞Different segments have different function: Jejunum — lactose intolerance Antigen-independent Factors
☞Indication is mainly for short bowel syndrome with complications associated ☞Causes of Tissue Damage
with Total Parenteral Nutrition − Are the result of mechanical trauma as well as disruption of the blood
− Irreversible intestinal failure as well as congenital mucosal disorders supply as the graft is harvested
☞Performed in 1985 ☞Ischemia, hypothermia, reperfusion injury
− 65% are performed in children ☞Donor age (increasing rejection with age)
− 44% combined with therapy ☞Recipient body area (increasing rejection with increased area)
− 42% isolated ☞Diabetes in recipient
☞Indications ☞Asian Donor Race increases risk of graft failure
− Adults: ischemia (22%), crohn’s disease, trauma, desmoid tumors Long-term Complications
− Pedia: gastroschisis (27%), volvulus, NEC ☞The three most common causes of death after transplantation
− Cardiovascular disease(related to chronic use of steroid)
− Infectious disease (Effect of Immunosuppressants)
− Malignancy
☞Reflects chronic long-term immunosuppression particularly the infectious
and malignancy related deaths
☞The two most common causes of graft loss
− Death with a functioning graft
− Chronic rejection
Infection
☞Urinary tract infection is quite common
☞Cytomegalovirus (CMV)
☞Pneumocystis carinii
− High risk in T-cell deficient patients

☞Overall survival is 45% − Common in early graft course

− 70% in 1 year ☞HSV
− Full graft function 80% ☞Toxoplasma
☞Recovery ☞Hepatitis C Virus
− Tube feeding on 2nd week (low osmolality isotonic dipeptide) − Contributes to graft failure in chronic setting
☞Mortality − Immunosuppression promotes hepatitis C reactivation
− Sepsis is main cause of mortality (49%) − Donors should be screened for viral infections prior to transplantation
− Lymphoma ☞Pneumococcal Infection
☞Rejection ☞EBV
− Acute rejection occurs in 90% (ave. 3/px) 🎙 Update active vaccines for those receiving transplantations, and antimicrobial
− Most frequent and severe in SBTransplant alone
prophylaxis

🎙 Since multiorgan stransplant requires lesser immunosuppressant Transplant-associated Malignancy

− Graft dysfunction: no lab marker
☞The overall incidence of malignancy is approximately 6 percent
• CHO absorption (d-xylose) testing ☞1 to 2 percent are lymphomas
• 24-hour fecal fat content (0-8.5%) - fat cannot be absorbed, ☞Skin squamous cell carcinoma —most common cancer after transplantation
• Endoscopy surveillance
☞Kaposi’s sarcoma and genital neoplasms —may have been due to previous
exposure to HPV
☞Posttransplant lymphoproliferative disease (PTLD) are abnormalities driven
by Epstein-Barr virus (EBV)
☞A consequence of long term immunosuppression

Disclaimer: ppt and recording based only po hehe; use at ur own risk

Normal Graft Rejection

☞Contraindication
− Congenital immunodeficiency— high risk of GVHD
🎙 because the small intestines contain a lot of lymphoid cells (Peyer’s patches)
− CMV or EBV (-) recipient
FACTORS AFFECTING TRANSPLANT OUTCOME IN GENERAL

☞Early graft dysfunction and early graft ischemia

☞Previous graft rejection (that is, >1 transplant)
☞Presence of preformed anti HLA antibodies in serum of recipient
☞Early rejection episodes – even with successfully treated
i’m proud of you #

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