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Transplantation immunology
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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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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
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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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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There
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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
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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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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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
necrosis r hepatitis C
Heart- valvular heart disease or coronary artery
disease
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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
Recognition
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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
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.
Hereditary Viral
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
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
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
IPF CF
Alpha-1
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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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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.
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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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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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
Click to edit Master subtitle style
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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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
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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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
- person receives blood-forming stem cells from a genetically similar donor, but not identical
q
Autologous - blood-forming stem cells are removed, stored, and later given back to the same person
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Chemotherapy
- 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
Positron emission tomograph (PET) scan Compatibility of the donor and recipient
Psychosocial status
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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
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.
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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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.
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
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Mechanisms of Rejection
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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+
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
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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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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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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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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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
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Principal Occurs
Acute Rejection
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
Acute Rejection
ACUTE
LATE REJECTION
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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
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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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
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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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
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
Tacrolimus
A macrolide Derived 5/23/12
Sirolimus (Rapamune)
Resembles tacrolimus Inhibits the activation and proliferation of T lymphocytes
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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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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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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Hair
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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