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Transplantation immunology

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Click to edit Master subtitle style

Solid organ transplantation

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Transplantation

Process of taking cells, tissues, or organs called GRAFT, from individual and placing them into a different individual. the individual who provides the graft the individual who receives the

DONOR-

RECIPIENT-

graft.
Orthotropic

Transplantation- the graft is placed into its normal anatomic location. Transplantation- the graft is placed in a different site.

Heterotropic
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 Autologous Syngeneic Allogeneic

graft (Autograft)- graft transplanted from one individual to the same individual. graft- graft transplanted between two genetically identical or syngeneic individuals. graft- (Allograft) graft transplanted between two genetically different individuals of the same species.
Alloantigen molecules that are recognized as

foreigned in allografts.
Xenogeneic

graft (Xenograft) graft transplanted between two individuals of different species.

Xenoantigen molecules that are recognized as

foreigned in xenografts.
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HISTOCOMPATIBILITY ANTIGENS
The major histocompatibility complex (MHC) is a cluster of genes found on the short arm of chromosome 6 at band 21(6p21) Any of the genetically determined antigens on the surface of cell membranes, serve to identify a cell as self or nonself.

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NOMENCLATURE OF HLA ALLELES

Each HLA allele name has a unique number corresponding to up to four sets of digits separated by colons the first two digits describe the type ,which often corresponds to the serologic antigen carried by an allotype. the third and the fourth digits used to list the subtype , numbers being assigned in the order in which DNA sequences have been determined.
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Alleles differ in one or more nucleotide substitutions change the amino acid sequence of the encoded protein Alleles that differ only by synonymous nucleotide substitutions (silent or non-coding substitutions) Alleles that only differ by sequence polymorphisms in the introns or in the 5' or 3' untranslated regions that flank the exons and introns

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 unique allele number -additional optional suffixes that may be added to an allele to indicate its expression status N (null) L (low) S (secreted) C (Cytoplasm) A (Aberrant)

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MHC REGIONS
MHC is divided into fur region (D,C,B,A) A,B,C REGION classic or class 1a genes that code for class I molecule D REGION- codes for class II molecule

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Classes of HLA molecule

class I HLA molecules consist of an alpha chain, a highly polymorphic glycoprotein, encoded within MHC on chromosome 6.

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 There

are 3 major and 3 minor MHC class I genes in HLA:

HLA-A HLA-B HLA-C minor

genes are HLA-E, HLAF and HLA-G

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class II HLA molecules are composed of alpha chain and beta chain that are encoded within the MHC.

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 Major

MHC class II

HLA-DP
-chain encoded by HLA-DPA1locus -chain encoded by HLA-DPB1locus

HLA-DQ
-chain encoded by HLA-DQA1 locus -chain encoded by HLA-DQB1 locus

HLA-DR
-chain encoded by HLA-DRA locus 4 -chains (only 3 possible per person), encoded

by HLA-DRB1, DRB3, DRB4, DRB5loci

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HLA TYPING
a potential recipient needs to have HLA typing a family may be conducted for a suitable donor , if a suitable match is not found, the patient is place n a waiting list. Polymerase chain reaction- newer method f HLA typing followed by probing with sequence-specific oligonuceotide probes (SSOPs) and PCR amplification of alleles at loci using allele-specific primer.
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HLA genotype matched- means HLA-identical sibling, when all allele are truly identical. zero-mismatched- unrelated donors may be mismatched because typing does not distinguish between very close related allele

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Typing method
SEROLOGY

used to be the gold standard. Now being superceded by molecular techniques as they become more robust and time efficient rarely used now. Orginally used for Class II typing fast becoming the method of choice. Many laboratories test of choice

CELLULAR

MOLECULAR

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COMPLEMENT-MEDIATED CYTOTOXICITY
lymphocyte microcytotoxicity method- a technique which a battery of reagent antisera and isolated target cell are incubated with a source of complement under oil to prevent evaporation for HLA class I typing or anti-class I antibdy identification, the purified T-cell population is preffered because human T lymphocyte express class I not class II molecules
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class II HLA-DR and HLA-DQ are recognized by similar serologic method, except that isolated B cell are the usual target because their surfaces is rich in this molecule also in class I determinants class III cmplement are recognized by the availability of diagnostic reagent, butreagent remain scarce.

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Solid-phase Enzyme-Linked Immunosorbent Assay

ELISA is available for panel-reactive antibdy (PRA) determination and antibdyspecific analysis. ELISA-based HLA are considered reproducible,sensitive and objective.

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FLOW CYTOMETERY
is a technique for counting and examining microscopic particles, such as cells and chromosomes single-cell analysis is the most sensitive method for crossmatching and antibody identification alternative fow cytometry format uses microparticles coated with HLA antigens f known specificity
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FACTS ABOUT SOLID ORGAN TRANSPLANTATION

organ transplantation is widely viewed as the preferred treatment for end-stage organ failure because of the quality of life treatment offers for patients and because of long term benefits.

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FACTORS ON HOW LONG A PATIENTS WAITS FOR A TRANSPLANT Blood type

Tissue type Height and weight of transplant candidates Sized of donated organ Medical urgency Time on the waiting list Distance between donors hospital and potential donor organ of donors in local area over

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In 1984 the U.S. Congress passed the National Organ Transplant act. August 14, 2007 the United Network for Organ Sharing patient waiting list contained 96,991 names. Most common reasons for needing a transplant vary by the type of organ.
Kidney- diabetes, glomerulonephritis, hypertensive

nephrosclerosis or polycystic kidney

Liver- cholestatic liver disease, acute hepatic

necrosis r hepatitis C
Heart- valvular heart disease or coronary artery

disease
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Click to edit Master subtitle style

Immune response to allografts

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Recognition of Alloantigens
Recognition

of transplanted cells as self or foreign is determined by polymorphic genes that are inherited from both parents and are expressed codominantly. (Major Histocompatibilty Complex) molecules are responsible for almost all strong (rapid) rejection reactions. can be a DIRECT or INDIRECT recognition Recognition

MHC

It

Direct

Allogeneic MHC molecules may be presented on donor

APCs to recipient T cells.

Indirect

Recognition

5/23/12 The alloantigens may be picked up by host APCs that

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TYPES OF TRANSPLANT

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KIDNEY
The

kidneys' function are to filter the blood, remove wastes, control the body's fluid balance, and regulate the balance of electrolytes. cause of kidney transplant is the end-stage kidney failure.

Common

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 Kidney

Transplant is a surgical procedure to place a functioning kidney from a donor into a person whose kidneys no longer function properly. The first successful human kidney transplant was performed in 1954 between monozygotic twins.

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HEART VALVE
A heart

valve normally allows blood to flow in only one direction through the heart. Xenogeneic valve replacements are a standard modality for the treatment of aortic and mitral valve defects. Most of the heart valve transplant patients are not immunosuppressed.

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Two kinds of prosthetic heart valves are available: made of man-made Mechanical -materials, such as metal or ceramic.
Biological

-- made of human or animal

tissue.

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HEART
The

heart is a vital organ that basically serves as a pump. transplant is a procedure in which a surgeon removes a diseased heart and replaces it with a donor heart.

A heart

The

first successful allograft cardiac transplant was performed in 1967 by Dr. Christian Bernard in Cape Town, South 5/23/12 Africa.

Their heart failure might have been caused by:

Coronary

heart disease. conditions.

Hereditary Viral

infections of the heart. heart valves and muscles.

Damaged
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CORNEA
The

cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. transplantation is the replacement of the patients own cornea with one donated by a deceased person.

Cornea

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SKIN
Skin Skin

is the outer covering of the body.

Grafting or Skin Transplanting is a type of medical grafting involving the transplantation of skin. Skin grafting is often used to treat: wounding or trauma

Extensive Burns Areas

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of prior infection with extensive skin

loss

LIVER

Liver is an organ in the upper abdomen that aids in digestion and removes waste products and worn-out cells from the blood. Liver transplantation is surgery to remove a diseased or injured liver and replace it with a healthy whole liver or a segment of a liver from another person.

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 About

70% of all liver-transplant patients have some degree of organ rejection prior to discharge. Anti-rejection medications are given to ward off the immune attack. first human liver transplant was performed in 1963 by a surgical team led by Dr. Thomas Starzl of Denver, Colorado, United States.

The

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LUNGS

Lungs are a pair of breathing organs located in the chest which remove carbon dioxide from and bring oxygen to the blood. transplant is surgery to remove a person's diseased lung and replace it with a healthy lung from a deceased donor.

A lung

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 Lung

transplants aren't very common because of the small number of donor organs available. successful lung transplants have been difficult to achieve because the lungs are susceptible to infection.

And

Common

infection among potential donors is SEPSIS, it is a serious infection usually caused when bacteria make toxins that cause the immune system to attack the body's own organs and tissues. 5/23/12

Lung transplants most often are used to treat people who have severe:
COPD

(chronic obstructive pulmonary disease) (idiopathic pulmonary fibrosis) (cystic fibrosis)

IPF CF

Alpha-1
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antitrypsin deficiency (AAT deficiency)

PANCREAS
Pancreas

is a glandular organ that secretes digestive enzymes and hormones. transplant is a surgical procedure to place a healthy pancreas from a deceased donor into a person whose pancreas no longer functions properly. grafts have been successful

A pancreas

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Pancreas Transplant is usually done because of:

Type

1 diabetes that can't be controlled with standard treatment. insulin reactions. poor blood sugar control.

Frequent

Consistently Severe
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kidney damage.

The risks for pancreas transplant include:

Blood

clots (deep venous thrombosis)

Clotting

(thrombosis) of the arteries or veins of the new pancreas of certain cancers after a of the pancreas few years

Development Inflammation

(pancreatitis)
Leakage

of fluid from the new pancreas where it attaches to the intestine or bladder

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BONE
Bones

support, and protect the various organs of the body, produce red and white blood cells and store minerals. grafting is a surgical procedure by which new bone or a replacement material is placed into spaces between or around broken bone (fractures) or holes in bone (defects) to aid in healing.

Bone

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 Bone

marrow may be harvested from the hip (iliac bone) to serve as bone grafts elsewhere

in the body.
Bone

grafting is

used to repair bone fractures that are extremely complex, pose 5/23/12 a significant risk to the

Blood Transfusion
Refers The

to the transfer of circulating blood cells or plasma from one individual to another. most important alloantigen system in the blood transfusion is the ABO system. of the foreign RBC results to TRANSFUSION REACTIONS. Rhesus (Rh) antigen is another important red blood cell antigen that may be responsible for transfusion reactions.

Lysis The

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Click to edit Master subtitle style

Bone Marrow Transplantation

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The goal of transplanting bone marrow or peripheral blood progenitor cells is to achieve a potential cure or to help patients recover from Click to edit Master subtitle style high-dose chemotherapy that has destroyed stem or marrow cells, a condition known as myeloablation.

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Click to edit Master subtitle style

Cancers Treated with Progenitor Cell Transplants

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is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Acute Leukemia
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Leukemia

a rapid increase in the numbers of immature blood cells crowding due to such cells makes the bone marrow unable to produce healthy blood cells immediate treatment is required due to the rapid progression and accumulation of the malignant cells most common forms of leukemia in children

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Chronic Leukemia
excessive build up of relatively mature white blood cells, but still Clickabnormal to edit Master subtitle style typically taking months or years to progress sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy mostly occurs in older people

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Acute Lymphoblastic Leukemia

most common type of leukemia in young children - also affects adults, esp. those age 65 and older Click - to edit Master subtitle style rapidly progressive malignant disorder - production of immature WBCs
-

Acute Myeloid Leukemia

also referred to as, non-lymphoblastic leukemia - occurs in both adults & children
-

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Chronic Lymphocytic Leukemia

most often affects adults over age 55 - rarely affects children
-

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Chronic Myeloid Leukemia

occurs mainly in adults - affects a very small number of children
-

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Lymphoma
cancer that starts in white blood cells called lymphocytes usually edit abnormal type of B lymphocyte Click to an Master subtitle style named after Thomas Hodgkin, who first described abnormalities in the lymph system in 1832

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 Hodgkins

Non-Hodgkins

Lymphoma less common than non-Hodgkin's lymphoma

1%

Lymphoma more common than Hodgkin's disease

sixth

of all cancers in the U.S. cell

Reed-Sternberg

most common cancer among males and the fifth most common cancer among females to grow aggressively

tendency
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ReedSternberg cell:

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Diseases Treatable by Stem Cell Transplantation

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Progenitor Blood ability to evolve into different types of cells Click capable of reconstituting a persons immune system to edit MasterCells subtitle style

lymphocytes, granulocytes, macrophages, platelets CD34 antigen identifies a population of stem cells minimal dose of 2x106 CD34+ cells/kg patient weight

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Types of Transplantation
q

Allogeneic Click to edit Master subtitle style

- person receives blood-forming stem cells from a genetically similar donor, but not identical
q

Syngeneic - person receive stem cells from their identical twin

Autologous - blood-forming stem cells are removed, stored, and later given back to the same person

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Chemotherapy

Traditional Transplantation Click to edit Master subtitle style

- uses anti-cancer drugs to destroy cancer cells and prevent their growth. - chemotherapy drugs travel through your bloodstream t reach the cancer cells that have spread, it is often referred to as systemic therapy. - nausea, loss of appetite, hair loss, fatigue and weight changes

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Radiotherapy

- delivers measured doses of radiation directly to the site of the cancer cells or tumor *External beam radiation Click to edit Master subtitle style - is the most common type of radiotherapy used - is delivered from outside the body using machines called linear *Internal radiation, or brachytherapy, - is typically prescribed for those needing higher doses of radiation than the outer tissues of their body can handle - radioactive catheters (thin tubes) are placed directly into or near the tumor - side effects typically depend on the area of the body receiving the treatment - most common include fatigue, a redness or irritation of 5/23/12 your skin, nausea, diarrhea and inflammation inside

EVALUATION OF CANDIDATES FOR PBSC/BONE MARROW TRANSPLANT

Factors that influence Pre-transplant the eligibility for bone evaluation may include: HLA- tissuemarrow transplant include: typing
Age marrow biopsy and aspiration Bone
Echocardiogram Disease status (ECHO)/MUGA/Electrocardiogram (ECG) Dental exam status for the recipient Performance Blood tests Organ function Pulmonary disease status Infectious function tests (PFTs)

Positron emission tomograph (PET) scan Compatibility of the donor and recipient

Psychosocial status

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How is bone marrow obtained for transplantation?

BONE MARROW the procedure for obtaining bone marrow, which is called "harvesting," is similar for all three types of BMTs (autologous, syngeneic, and allogeneic). The donor is given either general anesthesia, which puts the person to sleep during the procedure, or regional anesthesia, which causes loss of feeling below the waist. Needles are inserted

How are PBSCs obtained for transplantation?

Peripheral Blood Stem Cell

The stem cells used in PBSCT come from the bloodstream. A process called apheresis or leukapheresis is used to obtain PBSCs for transplantation. In apheresis, blood is removed through a large vein in the arm or a central venous catheter.

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The blood goes through a machine that removes the stem cells. The blood is then returned to the donor and the collected cells are stored. Apheresis typically takes four to six hours. The stem cells are then frozen until they are given to the recipient.

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TRANSPLANTATION

After the bone marrow or PBSCs are transplanted into the recipient via a central catheter, the cells migrate to the bone marrow, where they begin to produce new blood cells in a process known as engraftment. Engraftment usually occurs within 2-4 weeks after infusion of stem cells. Complete recovery of immune function takes much longer, up to several months for autologous transplant reciepient and 1-2 years for allogenic transplant recipients. Patients receiving allogenic PBSCs are less likely to have infection than bone marrow recipients.

TRANSPLANT-RELATED COMPLICATION

Infection Graft vs. host disease (GVHD)

A. Acute graft vs. host disease - occurs w/n 3 months. The

skin, liver, intestine may be affected.

B. Chronic graft vs. host

disease may occur months or

even years after transplant. Skin is the most organ affected.

Organ toxicity Veno-occlusive Disease Lack of Engraftment

LATE EFFECTS

Growth and other endocrine (gland) problems may develop depending upon the type of conditioning used. Sterility is common for most patients. Organ Damage can occur to the liver, kidneys, lungs, or heart. Cataracts may develop clouding the lens of the eye and reducing vision.

Graft Manipulation and Storage

ABO incompatibility between donor and recipient is encountered in 23% to 30% of all hematopoeitic cell transplants. A major incompatibility exists between donor and recipient when the recipient possesses antibody against the RBC antigen of the donor, which would result in lysis of the transfused donor cells. Difference between donor and recipients ABO or Rh blood groups have no effect on bone marrow engraftment, rejection or GVHD. To prevent acute hemolysis, the main objective of the laboratory is to remove as many RBCs as possible while preserving the hematopoeitic progenitor cells to ensure timely engraftment. This is accomplished mainly by automated means. Removal of the plasma from the graft is used to minimize the risk of immediate hemolysis.

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Automated procedures involving apheresis equipment such as the COBE Spectra and Fenwall cs 3000 plus.

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Normal saline or other media was can be added to the product in a volume equivalent to about half the volume of the discarded plasma to dilute the remaining donor antibody and lower the hematocrit for easier infusion. With the development of Monoclonal Antibody, there has been an increase in stem cell selection and purging of grafts. These techniques have resulted in decrease tumor reinfusion into autologous recipients and decreases the amount of T-cells infused in allogenic reciepients. Cryopreservation preservation by freezing at very low temperature.

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TRANSPLANTS FROM UNRELATED DONORS

For those patients without a family donor, the National Marrow Donor Program (NMPD) provides a service to locate HLA-matched unrelated donors (MUD transplantation). Currently, there are approximately five million volunteer bone marrow donors registered with the NMDP. An additional 40,000 new donors are added to the registry each month and the NMDP facilitates over 1,000 MUD transplants each year.

GRAFT REJECTION (ALLOGRAFT

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 Transplant

rejection is a process in which a transplant recipient's immune system attacks the transplanted organ or tissue. an organ or tissue from one individual is transplanted into a genetically nonidentical other individual, a series of cellular and molecular events are initiated. This response involves reperfusion injury, innate and adaptive immune response and therefore a variety of partly overlapping pathophysiological processes.

When

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 Major

Histocompatibility Complex (MHC)

markers present on the surface of every cell

slightly different in different individuals.

Encoded in chromosome 6 Encodes the HLA (Human Leukocyte Antigen) HLA is determined by five different linked genes. genes are all polymorphic

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Mechanisms of Rejection

Cellular Mechanism Humoral Mechanism Molecular Mechanism

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 Variations

in the expression of class II histocompatibility antigens by different tissues and the presence of APCs in some tissues greatly influence the success of a transplant. immunity is the major effector mechanism in graft rejection. sites accessible to the immune system in the recipient are susceptible to graft rejection.

Cell-mediated

Only

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Cellular Mechanism
Primarily

regulated by the interaction of the host T cells with the antigens of the graft. by 2 mechanisms: destruction of graft cells by CD8+ CTLs delayed hypersensitivity reactions triggered by activated CD4+ helper cells.

Induced a) b)

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 The

recipients T cells recognize antigens in the graft (the allogeneic antigens, or alloantigens) by two pathways:
Direct Pathway Indirect Pathway

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Direct Pathway
T

cells of the transplant recipient recognize allogeneic (donor) MHC molecules on the surface of an antigenpresenting cell in the graft. cells
Carried by the donors organ most important immunogens because they

Dendritic

not only richly express class I and II HLA molecules but also are endowed with costimulatory molecules (B7-1 and B7-2)
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Direct Pathway
Both

the CD4+ and the CD8+ T cells of the transplant recipient are involved in this reaction. T cells
recognize class I HLA antigens and differentiate

CD8+

into mature CTLs.

dependent on the release of cytokines, such as IL-

2 (CD4+ THC) and CD40 ligand that activates APC to promote differentiation of CTLs.
Once mature CTL are generated, they kill the

graft.
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Direct Pathway
CD4+

T cells

triggered into proliferation and differentiation

into TH1 effector cells by recognition of allogeneic class II molecules.

cytokines secreted by the activated CD4+ T

cells cause increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages), and activate the macrophages, resulting in graft injury.

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Indirect Pathway
generates

CD4+ T cells that enter the graft and recognize graft antigens being displayed by host antigenpresenting cells that have also entered the graft, and the result is a delayed hypersensitivity type of reaction. CD8+ CTLs that may be generated by the indirect pathway cannot directly recognize or kill graft cells, because these CTLs recognize graft antigens presented by the hosts antigen-presenting cells.

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Humoral Mechanism (Antibodies)

The

ability to reject grafts cannot be transferred from one animal to another by means of passively injected antibody. not rule out the possibility that antibody can play a part in graft rejection because when serum, containing at best about 1% specific antibody, is injected into a recipient the diluting effect of the blood and tissue fluids considerably reduces the possibility of the antibody reaching the graft site in adequate concentration to influence the viability of the graft. antibodies evoked against alloantigens in the

does

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Humoral Mechanism
Deposits

of immunoglobulin and complement can be detected particularly in the walls of blood vessels.

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Molecular Mechanism
based

on recognition of foreign transplanted cells by the expression of polymorphic, codominant genes. genes code for protein molecules which are found on the surfaces of cells called antigens. to polymorphism, it is rare to find a donor and recipient with matching surface antigens. Major histocompatibility complex (MHC) molecules are responsible for the most rapid rejection reaction.

These

Due

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Types and Second Set Rejection of graft First Set Hyperacute Rejection rejection
Accelerated Rejection Acute Rejection Chronic Rejection

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First Set Rejection

Activation of cellular immunity by T cells. directly attack cellular antigens to which they are sensitized by previous exposure or by cytotoxic lymphokines. occurs within the first few days of transplantation, and the tissue is lost in 10-20 days.

Lymphocytes

Sensitization

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Second Set Rejection

Sensitized

lymphocytes are already present because of prior graft rejection. rejection of tissue results from regrafting. from a sensitized animal transferred to a first-graft recipient will accelerate rejection of the graft.

Accelerated

Lymphocytes

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First and Second Set Rejection

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Hyperacute Rejection

Occurs within minutes of transplantation and is characterized by thrombosis of graft vessels and ischemic necrosis of the graft. Mediated by circulating antibodies
IgM specific for blood group antigens Antibodies specific for allogeneic MHC

molecules Bind to antigens in the graft vascular endothelium and activate the complement and clotting systems leading to injury to the endothelium and thrombus formation. Major barrier to XENOTRANSPLANTATION.
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Hyperacute Rejection

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Hyperacute Rejection

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Hyperacute Rejection

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Accelerated Rejection
Comparable

to the second-set rejection phenomenon observed in animal models. is less severe than hyperacute rejection. of T cell mediated response. exposure to donor MHC molecules

Retransplantation Activation Prior

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 Principal Occurs

Acute Rejection

cause of early graft failure

within days or weeks

Mediated Early

mainly by T cells which react against alloantigens in the graft. processes appear to be cell-mediated later aspects may involve antibody and complement. EARLY REJECTION
Occurs up to about 10 days after transplantation Characterized by dense cellular infiltration and

ACUTE

rupture of peritubular capillaries.

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Cell mediated hypersensitivity reaction involving T

Acute Rejection
ACUTE

LATE REJECTION

Occurs 11 days or more after transplantation in

patients suppressed with prednisone and azathioprine.

Probably caused by binding of immunoglobulin,

presumably antibody and complement.

These Ig deposits on the vessel walls include platelet

aggregates in glomerular capillaries (ACUTE RENAL SHUTDOWN)

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Acute Rejection

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Acute Rejection

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Acute Rejection

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Chronic Rejection
Indolent Principal Process

form of graft damage cause of graft failure

results in a slow but continual loss of organ function over months or years. as fibrosis of the graft and by gradual narrowing of graft blood vessels, called arteriosclerosis.

Manifested

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Chronic Rejection

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Chronic Rejection

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REJECTIONS

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Rejections

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Graft Survival Rates

GRAFT When

SURVIVAL RATES

kidney transplants come from HLAidentical siblings, transplant recipients have a 5 year survival rate of more than 80% 70% two HLAs match, the graft survival is

When When

more than two HLAs are mismatched, the chances of graft survival are considerably lower

When

kidney transplants come from cadavers, regardless of matching, the 5 year survival rate is 33% to 50%. These figures are improving, 5/23/12 however, as a result of better management

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Immunosuppressive Therapies

immunosuppression

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Immunosupression
Inhibition of one or more components of the adaptive and innate immunity system, resulting from underlying disease or intentionally induced by drugs for the purpose of preventing or treating graft rejection or autoimmune disease. Used for the following:
Induction Maintenance of transplants Reversal of established rejectors
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Types of Immunosuppressive Treatments Azathioprine

Corticosteroids Cyclosporine Tacrolimus Sirolimus Mycophenolate Antilymphocyte

Mofetil (Antithymocyte) Globulin

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Azathioprine
An

oral purine analog that is antimetabolite with multiple activities, has been the mainstay of antirejection therapy. at an early stage in either T-cell or B-cell activation during the proliferative cycle of effector lymphocyte clones. in preventing acute rejection
Inhibits the primary immune response Little effect in secondary immune response Adverse effects include bone marrow

Acts

Useful

suppression,myopathy,alopecia,pancreatitis and hepatitis A.

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Corticosteroids
Used

in conjunction with azathioprine or another immunosuppressants such as cycloserine. inhibit T-cell proliferation dose is used to treat acute rejection from fungus Tolypocladium inflatum

Directly High

Cyclosporine A
Isolated Inhibit

induction of cytotoxic T cells.

Tacrolimus
A macrolide Derived 5/23/12

with mechanism similar to cyclosporine. from Streptomyces tsukub

Sirolimus (Rapamune)
Resembles tacrolimus Inhibits the activation and proliferation of T lymphocytes

and subsequent production o IL-2, IL-4 and IL-15. allograft rejection.

An adjunctive agent for the prevention of acute renal

Myecophenolate Mofetil

Inhibits T and B lymphocyte proliferation and antibody formation by B lymphocytes. Efficacious as both prophylactic and rescue therapy in refractory renal allograft rejection. Preventing or reversing rejection in renal allograft recipients is well established.

Antilymphocyte Globulin

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GRAFT VS.HOST DISEASE

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AcuteGVHD
usually develops within three months of the transplant and occurs in 20 percent to 25 percent of HLA-matched sibling transplants in children and 30 percent to 35 percent in adults. Acute GvHD is more common in patients undergoing unrelated transplants, in particular if there is an HLA-mismatch. It usually happens within the first 3 months after transplant.
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Common acute symptoms include:

Abdominal pain or cramps

Diarrhea Fever Jaundice Skin

rash loss

Vomiting Weight
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To minimize the risk of graft rejection and GVHD, allogeneic BMT patients are given drugs to prevent GVHD before and after transplant that suppress the immune system. Use of these drugs, however, increases the risk of infection.

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 Precautions

taken to limit the patient's exposure to harmful bacteria, viruses and fungi during this period may include special air-filtering equipment in the patient's room, frequent handwashing by visitors, use of masks, gloves and robes by the patient and/or visitors, and elimination of fresh fruits, flowers and vegetables from the patient's environment which may harbor potentially harmful bacteria.

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Chronic GVHD
usually

develops after the third month post-transplant. Scientists believe that new T-cells produced after the donor's bone marrow has engrafted in the patient may cause chronic GVHD. It can also attack glands in the body that secrete mucous, saliva or other lubricants. Patients with chronic GVHD usually experience dryness or stinging in their eyes because the glands that secrete tears are impaired. 5/23/12

 Glands

that secrete saliva in the mouth are often affected by chronic GVHD and, less often, those that lubricate the esophagus, making swallowing and eating difficult. It's common for patients with chronic GVHD to experience a burning sensation in their mouths when using toothpaste or eating acidic foods. Good oral hygiene is imperative to minimize the risk of infection.

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Chronic symptoms may include:

Dry

eyes and dry mouth loss and digestive tract disorders

Hair

Hepatitis Lung Skin Skin

rash thickening

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 Chronic

GVHD is usually treatable with steroids such as prednisone, ozothioprine and cyclosporine, which suppress the patient's immune system. Antibiotics such as Bactrim or penicillin or both are usually taken to reduce the risk of infection while chronic GVHD is being treated.

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 In

addition, patients may be required to wear face masks while around other people, stay out of crowds, and avoid fresh plants, fruits and vegetables. Patients with chronic GVHD are usually advised to avoid vaccinations with live viruses such as German measles, tetanus, polio, etc. until the GVHD problem is completely resolved and use of immunosuppressive drugs ends.

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THANK YOU :D

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