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TRANSPLANT MEDICINE: PART-1

Author: akil, Posted on Saturday, September 25 @ 04:13:55 IST by RxPG  

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TRANSPLANTATION MEDICINE

In this article:
CLASSIFICATION
TRANSPLANTATION IMMUNOLOGY
CLINICAL INDICATIONS
MEDICAL MANAGEMENT
1. Blood and Tissue Typing
2. Immunosuppression
3. Antimicrobial Medication

In part 2:
COMPLICATIONS
1. Rejection
2. Medication-Induced Complications
3. Immunosuppression-Induced Complications
4. Specific Organ/Hematopoietic Cell Transplantation
5. Complications
PROGNOSIS
ORAL HEALTH CONSIDERATIONS
1. Oral Lesions
2. Dental Management
CONCLUSION

Organ transplants are mainly used to treat various life-threatening end-stage diseases. Technologies such as cold ischemia and preservation solutions allow for approximately 6 hours of “nonfunctioning” time for hearts and other organs, and 24 hours (or longer) for kidneys.
Dr. Joseph Murray performed the first human renal transplantation in 1954. He successfully transplanted a kidney from an identical twin to his brother.
The first successful allogeneic (not genetically identical) transplantation was a kidney transplantation performed in 1959 in which the recipient was “conditioned” (immunosuppressed to prevent rejection) by total body irradiation.
In 1962, a successful cadaveric donor renal transplant was achieved.
in 1966, a pancreas transplantation was successfully performed.
In the following year, the first human liver transplantation was performed, resulting in a 13-month survival.
In the same year, a heart was transplanted.
In 1968, a genetically related bone marrow transplantation (BMT, today referred to as a hematopoietic cell transplantation [HCT]) was performed;
In 1973 a genetically unrelated HCT was performed.
Lung transplantation has also been performed both as a single procedure and in combination with a heart transplantation.
The first heart-lung transplantation in the United States was done in 1981, and the first single lung transplantation in Canada was performed in 1983. Other organs that have been successfully transplanted include the small bowel, the skin, various limbs, and components of the human eye.


CLASSIFICATION
Broadly divide clinical transplants as being either a solid organ/tissue or an HCT. Virtually all types including hearts, lungs, kidneys, livers, intestines, pancreas, skin, eye components, and limbs.
Another type of transplant frequently used to treat various hematologic and nonhematologic malignancies/disorders is known as HCT.

TYPES OF GRAFT PROCEDURES:

Autograft Autologous Transplant from self A transplant to and from one’s self (autograft) is known as an “autologous transplant.”

Isograft Syngeneic Transplant between genetically identical individuals (monozygotic twin )
A transplantation from an identical twin (identical genetic makeup) is known as an “isograft,” with the process of this type of
transplantation known as “isogeneic or syngeneic transplantation.”

Allograft Allogeneic Transplant from a genetically different Most transplants are from donors that are not genetically identical to the recipient (allografts). These types of transplants are known as “allogeneic transplants.”

Xenograft Xenogeneic Transplants between different species Finally, transplants from donors of one species to recipients of another species (xenografts) are known as “xenogeneic transplants”

Due to the scarcity of isografts and the obvious limitations to autografts, allogeneic transplants are most commonly used today.
The success of allogeneic transplantation relies on sophisticated mechanisms for identifying and matching specific genetic markers between the donor and the recipient, as well as suppressing the recipient’s immune system to prevent transplant rejection. These are the concepts that serve as the basic foundation in transplantation medicine.

Tissue xenografts, which have been treated to reduce their immunogenicity, have been a successfully used treatment modality in some applications (ie, porcine heart valves), but whole organ xenografts have been unsuccessful. Research regarding genetically altered xenografts is ongoing. When the important immunologic barriers to xenogeneic transplantation are eliminated, the use of animal donors may possibly alleviate the relative paucity of available organs. Of course, significant ethical questions, as well as transplant
longevity and transmissible infectious diseases from animals, are questions that must be entertained before these types of transplants become commonplace.

Transplant Immunology:
Lymphocytes, particularly T lymphocytes (T cells), are instrumental in transplantation failure and are stimulated during rejection.
A donor’s major histocompatibility complex (MHC), a genetic region found on the short arm of chromosome number 6 of all mammalian cells, codes for products (antigens) that allow immune cells to identify “self” from “non-self.”
In humans, the “self-antigens” encoded by the MHC include the human leukocyte antigen (HLA) system. Although there are many other gene products, from more than 30 histocompatibility gene loci, that can stimulate graft rejection, it is the HLA system that produces the strongest immunologic response.MHC genes are inherited from each parent; every child has components of both mother’s and father’s HLAs on their cell surfaces. The MHC/HLA system is broadly divided into regions.
MHC class I and class II regions are those significantly involved in rejection. MHC class I regions include HLA-A, -B, -C, -E, -F, and -G. (The present role of the E, F, and G regions in transplantation is not well understood.)
MHC class II regions include HLA-DR, -DQ, -DP, -DO, and -DN. MHC class II genes
Today, deoxyribonucleic acid (DNA)–based typing (see below) has led to a more specific and detailed classification of the transplantation genes, such that the HLA alleles are related to their DNA sequences.
HLA class I antigens are expressed on most nucleated cells and on red blood cells.
class II antigens are expressed only on antigen-presenting cells (APCs) that include macrophages, B cells, dendritic cells, and some endothelial cells. The expression of these MHC gene products (antigens) on a cell’s surface is regulated by various cytokines such as interferon-.(IFN-.) and tumor necrosis factor (TNF). Transplanted foreign MHC molecules activate the immune response by stimulating the recipient’s T cells to respond to foreign antigens. The interaction of the MHC of the donor cells with the recipient’s T-cell receptor initiates the immune reaction. T cells can be activated either by the donor’s or the recipient’s APCs, resulting in expression and production of lymphokines and cytokines that promote activation of cytotoxic T cells, activation of B cells, and activation of natural killer cell activity as well as promote enhanced expression of MHC and increased macrophage activity. This, in turn, causes further immune reactions that result in direct tissue damage and damage to the vascular endothelium of the graft, which may ultimately result in graft rejection.

Transplant Rejection:
It may be an acute process occurring within days to weeks of the transplantation surgery. This acute process is related to the primary activation of T cells and usually can be reversed by changing the immunosuppressive medication or the medication regimen.

Chronic rejection of the transplanted organ is also a significant problem leading to organ failure. This type of rejection is slow and insidious and cannot be reversed. It probably occurs by continued, albeit muted, cell-mediated toxicity that results in vascular changes to the transplanted organ (as well as other actions, which have not been fully elucidated), leading ultimately to graft rejection.

Another type of rejection is known as “hyperacute rejection”; this occurs within minutes to hours after a transplant procedure. This pattern of rejection occurs in patients who have undergone previous transplantations, patients who have had multiple pregnancies, and patients who have had multiple blood transfusions. It is caused by “preformed” antidonor antibodies that activate complement, resulting in a severe attack of the graft, which often cannot be reversed.

Type of Rejection Description
Acute Usually occurs within days to weeks due to primary activation of the T-cell response
Chronic Usually occurs months to years after transplantation; probably occurs by continued, albeit muted, cellmediated toxicity and other unclear causes
Hyperacute Usually occurs minutes to hours after transplantation and is caused by preformed antidonor antibodies activating complement

CLINICAL INDICATIONS

Type of Transplant Indications
Kidney End-stage renal disease
Glomerulonephritis
Pyelonephritis
Congenital abnormalities
Nephrotic syndrome
Liver End-stage liver disease
Primary biliary cirrhosis
Biliary atresia (children)
Chronic hepatitis
Sclerosing cholangitis
Pancreas Severe diabetes leading to renal disease
Intestinal Massive short-bowel syndrome
Heart Cardiomyopathy
Severe coronary artery disease
Congestive heart failure
Heart and lung Multiorgan end-stage disease
Congenital abnormalities
Amyloidosis
Lung Primary pulmonary hypertension
COPD/emphysema
Pulmonary fibrosis
Cystic fibrosis
Hematopoietic cell Acute myelogenous leukemia
Acute lymphoblastic leukemia
Chronic myelogenous leukemia
Aplastic anemia
Multiple myeloma
Lymphoma (Hodgkin’s and non-Hodgkin’s)
Various solid tumors
Primary immunodeficiencies
? SLE/autoimmune disorders
COPD = chronic obstructive pulmonary disorder; SLE = systemic lupus erythematosus.
* Partial listing only.

MEDICAL MANAGEMENT
focuses on successfully preventing rejection.
When the donor and recipient tissue are genetically identical (autologous), the outcome of the transplantation is dependent solely upon the surgical success of the procedure. When tissue from genetically different sources is transplanted, a sophisticated means of preventing rejection must be instituted to ensure graft survival.
The success of an allogeneic transplantation relies on the ability to identify and match certain genetic markers between the donor and the recipient, while suppressing the recipient’s immune system in
order to prevent rejection.

Blood and Tissue Typing
Blood and tissue matching are used today for all allogeneic transplants. Standard ABO and Rh ± blood typing are performed
to prevent red blood cell agglutination. In addition to blood typing, some method of tissue typing is usually performed (as timing allows) before solid allogeneic transplantations take place and always before allogeneic HCT. Tissue typing allows for matching of the HLA system of antigens found on donor and recipient cells. There is significant variation in HLA testing, depending on the methods employed. Furthermore, based on the type of organ to be transplanted, there is variation in the extent of testing needed to safely transplant the organ.

typing is mandatory in allogeneic HCT, but it may be less important in first renal transplantations and for graft survival in liver or heart transplantations.Tissue typing generally can be performed by serologic or DNA-based testing methods. Serologic testing methods for HLA class I antigen identification can be performed by adding antisera of known HLA specificity with complement to a donor sample. Death of the donor cells confirms that they carried the specific HLA antigen. This test usually can be conducted in a couple of hours.

Another test used to specifically determine HLA class II antigens is the mixed lymphocyte culture (MLC) reaction, in which test lymphocytes are incubated with cells expressing known HLA. This results in either proliferation of the stimulated cell or no reaction if the HLA region is the same. This test is time consuming, and because of the short viability of the donor organ/tissue, it is not practical to confirm HLA compatibility in some solid organ transplant.

DNA-based testing for tissue typing is being used more commonly today. Polymerase chain reaction (PCR) is used to identify the DNA in the HLA genes of both the donor and recipient cells. As DNA-based techniques become a more common method for tissue typing, HLA nomenclature will probably change to reflect DNA sequences rather than names that
have been serologically defined previously. Matching for all known HLA alleles is not practical. However, matching for specific MHC class I and class II antigens, especially HLA-A, -B, and -DR (and perhaps -DQ), is important for transplant success in HCT and renal transplantation. Cross-matching (crossing recipient serum with donor lymphocytes) is usually done to prevent hyperacute rejection in allogeneic solid organ transplants. This is a basic serologic test that is regarded as necessary in those allogeneic transplant recipients who have previously experienced massive immune challenges such as a prior transplantation, multiple pregnancies, or multiple blood transfusions. Since transplantation of solid organs (heart, lung, liver) often requires some expediency, time-consuming complex cross-matching or tissue typing cannot be performed. Instead, absence of antibodies to a panel of cells (defined in advance and known as “panel-reactive antibodies” [PRAs]) is usually adequate for heart and lung transplantation.Interestingly, MHC compatibility in liver transplantation seems negligible in achieving better outcomes.This is fortunate because the timing of liver transplantation often precludes HLA typing.

Immunosuppression
All allogeneic transplantations initially require immunosuppression if the transplanted organs are not to be acutely rejected. Furthermore, most allogeneic solid organ transplant recipients require lifelong maintenance immunosuppression. This may not always be the case with
HCT.

Additionally, more intensive immunosuppressive regimens are employed later in the post-transplantation period in cases of acute rejection episodes.

CYCLOSPORINE ANALOGUES

Cyclosporine (CSA) is a cyclic polypeptide macrolide medication derived from a metabolite of the fungus Beauveria nivea
It specifically and reversibly inhibits immunocompetent lymphocytes in the G0 and G1 phase of the cell cycle.
CSA binds with an intracellular protein, cyclophilin, and inhibits calcineurin. Which activates a nuclear component of T cells that is thought to initiate gene transcription for the formation of interleukin (IL)-2, reduces the expression of IL-2 receptors. T- helper and, to some extent, T-suppressor cells are preferentially suppressed.
This medication has some effect on humoral immunity
No effect on phagocytic function, neutrophil migration, macrophage migration, or direct bone marrow suppression.
A microemulsion formulation is used to enhance the drug’s bioavailability.

TACROLIMUS
Tacrolimus (FK-506) is a macrolide immunosuppressant produced by Streptomyces tsukubaensis
This medication is similar to CSA - suppresses cellmediated reactions by suppressing T-cell activation.
Tacrolimus inhibits calcineurin by interacting with an intracellular protein known as the FK-binding protein. Consequently, T cells are not activated, and cell-mediated cytotoxicity is impeded.
Lower incidence of rejection with the use of tacrolimus as compared with the use of CSA in liver, kidney, and lung transplantations.

SIROLIMUS
Sirolimus (Rapamycin) is another macrolide immunosuppressive agent; produced by Streptomyces hygroscopicus.
used for prophylaxis against acute rejection of various organs and may be appropriate for use in chronic rejection.
Sirolimus’s mechanism of action is somewhat unique. Sirolimus inhibits the activation of a particular cellular kinase (target of rapamycin), which then interferes with intracellular signaling pathways of the IL-2 receptor, thereby preventing lymphocyte activation. The response of T cells to IL-2 and other cytokines is inhibited. Specifically, the overall effect is interference of T-cell activation during the cells’ G1 to the S phase. Sirolimus is recommended to be used in conjunction with CSA and corticosteroids. This medication has been shown to reduce acute rejection in the first 6 months following renal transplantation, compared with rejection rates when azathioprine is used.

AZATHIOPRINE
Azathioprine (AZA) is an antimetabolite that inhibits ribonucleic acid (RNA) and DNA synthesis by interfering with the purine synthesis that results in decreased T- and B-cell proliferation. It does not interfere with lymphokine production but has significant anti-inflammatory properties.

AZA can be bone marrow suppressive, leading to pancytopenia,
Cause significant liver dysfunction. Significant drug interactions with allopurinol and ACE inhibitors
AZA +CSA + corticosteroids as triple immunosuppressive therapy.

MYCOPHENOLATE MOFETIL
MMF, an ester of mycophenolic acid, is an antimetabolite that is used for prophylaxis against graft rejection, and that may have some action in reversing ongoing acute rejection. It inhibits inflammation by interfering with purine synthesis. Both T cells and B cells, which are dependent on this synthesis for their proliferation, are prevented from reproducing. Additionally, MMF interferes with intercellular adhesion of lymphocytes to endothelial cells. It does not inhibit IL-1 or IL-2 but may inhibit medial smooth-muscle proliferation.
Based on a multicenter trial, it is thought that this medication can replace AZA in a triple-drug regimen in kidney and heart transplantation.Although the incidence of graft rejection episodes is less with MMF, 1-year renal transplant-graft and patient survival have not been significantly improved by the use of MMF.



Major Immunosuppressive Agents*Drug

Type Indications Major Side Effects† Dental Implications†

Cyclosporine
Macrolide immunosuppresant Prophylaxis against organ rejection Hepatotoxicity Immunosuppressant‡
Calcineurin inhibitor Nephrotoxicity P-450 metabolized§
Elevation of blood pressure
Gingival hyperplasiaMonitor CV systemMay effect renal elimination of some drugsRisk of neoplasm
Tacrolimus
Macrolide immunosuppressant Prophylaxis against organ rejection Hepatotoxicity Immunosuppressant‡
Calcineurin inhibitor
Neurotoxicity P-450 metabolized§
Nephrotoxicity Monitor CV systemPost-transplant diabetes mellitus May effect renal elimination of some drugsElevation of blood pressure Risk of neoplasm

Sirolimus
Macrolide immunosuppressant Prophylaxis against acute and perhaps Hyperlipidemia Immunosuppressant‡
chronic organ rejection Hypertriglyceremia
P-450 metabolized§
Monitor CV systemMay effect renal elimination of some drugsRisk of neoplasm

Azathioprine Antimetabolite Prophylaxis against organ rejection
Bone marrow suppression Immunosuppressant ‡
Hepatotoxicity Risk of neoplasm

Mycophenolate mofetil Antimetabolite Prophylaxis against organ rejection and Leukopenia Immunosuppressant‡
possible agent to reverse ongoing Absorption is altered by antibiotics, antacids,
acute rejection and bile acid binders
Risk of neoplasm
ATG/ALG Polyclonal antibody Conditioning agents used prior to transplant Leukopenia Immunosuppressant‡
Pulmonary edemaRenal dysfunction

Muromonab-CD3 Monoclonal antibody Reversal of acute organ rejection, including Cytokine release syndrome Immunosuppressant‡
steroid-resistant acute rejection Interacts with indomethacinDaclizumab and basiliximab Monoclonal antibodies Reversal of acute organ rejection Pulmonary edema Immunosuppressant‡
Renal dysfunction Risk of neoplasm
Corticosteroids Nonspecific immunosupressant Reversal of acute organ rejection Multiple# Broad nonspecific immunosuppressant‡
Avoid NSAIDs and ASAMonitor CV systemPoor wound healingRisk of neoplasmSteroid supplement may be needed withstressful procedures
ASA = acetylsalicylic acid; ATG/ALG = antithymocyte globulin/antilymphocyte globulin; CV = cardiovascular; NSAIDs = nonsteroidal anti-inflammatory drugs.
‡Use of an immunosuppressant results in an increased risk of infection.
§Dental/oral pharmacotherapeutics that are metabolized by the liver’s cytochrome P450 3A system alter this drug’s serum levels. This group of medications includes, but is not limited to, erythromycin, clarithromycin, “azole” antifungals, benzodiazepines, carbamazepine, colchicines,, prednisolone, and metronidazole.

MUROMONAB-CD3
Muromonab-CD3 is a murine monoclonal antibody (IgG2A) to the CD3 receptor on mature human T cells. It is indicated for reversal of acute allograft rejection and cases of corticosteroid-resistant acute rejection. Monoclonal antibodies in general are effective immunosuppressants. They act by various mechanisms including cell depletion (via opsonization or complement fixation) and antigenic modulation. Cell depletion occurs by phagocytosis or cell lysis. Cell surface coating acts to interfere with cell-to-cell interaction. Antigenic modulation works via redistributing antigen/antibody complexes on the cell surface by internalizing certain receptors or
shedding them. OKT3 blocks the generation and function of cytotoxic/mature T cells. This drug is effective for approximately
1 week; approximately 3 days after administration, the patient has no detectable circulating mature T cells. There may
be some neutralizing antibodies to OKT3.

ANTITHYMOCYTE AND ANTILYMPHOCYTE GLOBULIN
Polyclonal antilymphocyte sera, antilymphocyte globulin (ALG), and antithymocyte globulin (ATG) are part of the same medication class. These agents are produced by immunizing animals with human lymphoid cells; the animals then produce antibodies to reduce the number of circulating T cells. Individually, these agents affect lymphocyte immunosuppression by reacting with common T-cell surface markers, then coating (opsonizing) the lymphocyte—marking it as foreign for phagocytosis. Polyclonal antibodies are used as conditioning agents prior to transplant.

DACLIZUMAB AND BASILIXIMAB
Daclizumab and Basiliximab are newer agents (synthetic monoclonal antibodies) used for reversal of acute organ rejection. They may also have a significant role during induction immunosuppression.35 These monoclonal antibodies bind the CD25 receptor (IL-2 receptor) on the surface of activated T cells (IL-2 receptor antagonists), preventing the expansion of CD4 and CD8 lymphocytes. They may be effective in conjunction with MMF and corticosteroids to eliminate the need for CSA use in the early post-transplant period.35 Anti-CD25 agents have also been reported to be efficacious in treatment of corticosteroid-resistant graft-versus-host disease (GVHD).36 Other promising targets for monoclonal antibody immunomodulation are being studied currently. The target receptors vary in their function, but development of target-specific medications will probably aid in selected immunosuppression.

CORTICOSTEROIDS
Corticosteroids are consistently used in all allogeneic ransplantations for prophylaxis against graft rejection and for reversal of acute rejection. The mechanism of action of this medication is extremely nonspecific as it affects the immune system in many complex ways. Steroids have anti-inflammatory effects and are able to suppress activated macrophages. They also interfere with antigen presentation and reduce the expression of MHC antigens on cells. Steroids reverse the effect of INF-.and alter the expression of adhesion molecules on vascular endothelium. These medications also have significant
effects on IL-1 activity and block the IL-2 gene and its production.

OTHER CYTOTOXIC AGENTS
Cytotoxic agents that are used in conditioning bone marrow prior to HCT include medications, specifically busulfan and/or cyclophosphamide, and also total body irradiation. They cause bone marrow suppression, resulting in pancytopenia (loss of cellular blood elements such as leukocytes and thrombocytes). Cytotoxic therapies are designed to destroy malignant cells, totally immunosuppress the recipient, and make room in the recipient’s bone marrow for the HCT. As a result of these
agents, the patient is not only highly susceptible to infection but is at a significantly high risk for bleeding.

NEWER IMMUNOSUPPRESSIVE STRATEGIES
Novel approaches to immunosuppression are currently being developed. The definitive immunosuppressive agent would be an agent that is able to destroy only the T cells that are involved with graft rejection, while leaving the remainder of the T cells and the immune system intact. Other monoclonal antibodies are currently under development, with promising immune modulation targets including more specific T cells and natural killer cells as well as endothelium-activated cells.FTY720 is a new immunosuppressive compound that may cause antigen-induced apoptosis (programmed cell death)of cytotoxic T cells; it is presently being studied in clinical trials.This agent exhibits no inhibition on the production of IL-2 or IL-3 but seems to act synergistically with CSA. Further study of this agent’s mechanism of action is warranted.Another promising approach to chemically induced immunosuppression is via a class of agents called the “T-cell co-stimulatory pathway modifiers.”Studies have suggested that immune system function has significant self-regulatory capabilities. It is now well recognized that T-cell receptors (TCRs) must recognize MHC-presented antigens to activate a T-cell response. However, it is also thought that TCR recognition requires two specific signals to stimulate T-cell activation—that is, recognition of both the TCR signal and a costimulatory receptor(s) such as CD28 and/or CD40 ligand, both mandatory for T-cell activation. Blocking of the co-stimulatory signal is the basis of this novel approach to preventing rejection of an allogeneic transplant. Another interesting finding that has been reported is that use of pravastatin during the early transplantation period may have some effect as an adjunct in immunosuppressive therapy
via reduction in natural killer cell cytotoxicity.Although newer immunosuppressive agents have been developed and are being used, they have not shown any clear benefit in patient or organ survival over CSA or tacrolimus. The newer agents, however, have shown some promise in reducing the incidence and severity of rejection. These newer agents probably have a role in reducing the need for cortico-steroids as well as reducing the toxic profiles of CSA or tacrolimus.Clinical studies to prove a possible synergistic interaction between sirolimus and CSA in reducing renal graft rejection may, in the future, reduce the need for steroids and CSA.Thus far, sirolimus has been approved as an adjuvant to CSA.Ultimately, graft and patient survival profiles coupled with side effects will determine the best antirejection “cocktail” to
be used in various transplantations. A different strategy, aimed at reducing the need for profound immunosuppression, is pretreatment of the recipient with donor blood. This procedure may extend graft survival, as evidenced in some animal models, by enhancing chimerism (ability of both donor and recipient immunocompetent cells to coexist). This concept of transplantation tolerance, whereby the recipient’s immune system is first significantly stimulated and then muted, was initially described by Starzl in 1963. The exact mechanism is speculative, but it has been verified in experiments. Starzl described low-level leukocyte chimerism in patients that received allografts and postulated that coexisting donor and recipient leukocyte populations lead to a down-regulated immune response to donor antigens. This is not to suggest that immunosuppression is not needed during the transplantation process but, rather, that if donor immunocompetent cells are transferred with the organ, they can take residence in the recipient’s bone marrow and perhaps allow for coexistence and tolerance. Protocols have been developed to infuse donor bone marrow at the time of transplantation, and they are presently being explored.

Antimicrobial Medication
In addition to immunosuppressive medication regimens, antimicrobial medication regimens are important in preventing infection in the transplant recipient. These regimens vary from center to center and from program to program. Patients with a transplant usually need prophylactic antibiotic, antifungal, and, in some cases, antiviral preparations. These medications may include sulfamethoxazole/trimethoprim, nystatin, fluconazole, acyclovir, ganciclovir, and others. Recently, the Centers for Disease Control and Prevention (CDC) has published guidelines for preventing opportunistic infections among HCT recipients.During the HCT process, all patients take multiple broad-spectrum antibiotics until their donated hematopoietic cells produce functional blood count levels. Additionally, most patients, especially those with a history of herpes simplex virus (HSV), take acyclovir. Various protocols have been proposed based on the type of transplant, the time frame after transplant, and the signs and symptoms that a transplant patient may experience.Antimicrobial medication coverage has proven to be effective in prevention of some of the transplant-associated infections,especially in HCT, but it still requires further study.Some have questioned whether antimicrobial agents are overused during the perioperative period in renal transplants.The CDC offers guidelines for HCT patients based on the quality of the evidence supporting the recommendation. The CDC also proposes guidelines for vaccination for HCT patients and for their family members/close contacts.Vaccination against hepatitis B and varicella-zoster viruses is usually considered if the transplant recipient does not have antibodies to these diseases. Special consideration for vaccination must be taken into account in the pediatric population. It is of utmost importance for children to receive appropriate vaccination.

HIGH YIELD POINTS:

Dr. Joseph Murray performed the first human renal transplantation in 1954.

TYPE OF GRAFT PROCEDURE DESCRIPTION

1. Autograft: Autologous Transplant from self A transplant to and from one’s self (autograft) is known as an “autologous transplant.”

2. Isograft: Syngeneic Transplant between genetically identical individuals (monozygotic twin ) :A transplantation from an identical twin (identical genetic makeup) is known as an “isograft,” with the process of this type of transplantation known as “isogeneic or syngeneic transplantation.”

3. Allograft : Allogeneic Transplant from a genetically different Most transplants are from donors that are not genetically identical to the recipient (allografts). These types of transplants are known as “allogeneic transplants.”

4. Xenograft: Xenogeneic Transplants between different species Finally, transplants from donors of one species to recipients of another species (xenografts) are known as “xenogeneic transplants”

CLINICAL INDICATIONS OF TRANSPLANTS

1. Kidney End-stage renal disease
2. Glomerulonephritis
3. Pyelonephritis
4. Congenital abnormalities
5. Nephrotic syndrome
6. Liver End-stage liver disease
7. Primary biliary cirrhosis
8. Biliary atresia (children)
9. Chronic hepatitis
10. Sclerosing cholangitis
11. Pancreas Severe diabetes leading to renal disease
12. Intestinal Massive short-bowel syndrome
13. Heart Cardiomyopathy
14. Severe coronary artery disease
15. Congestive heart failure
16. Heart and lung Multiorgan end-stage disease
17. Congenital abnormalities
18. Amyloidosis
19. Lung Primary pulmonary hypertension
20. COPD/emphysema
21. Pulmonary fibrosis
22. Cystic fibrosis
23. Hematopoietic cell Acute myelogenous leukemia
24. Acute lymphoblastic leukemia
25. Chronic myelogenous leukemia
26. Aplastic anemia
27. Multiple myeloma
28. Lymphoma (Hodgkin’s and non-Hodgkin’s)
29. Various solid tumors
30. Primary immunodeficiencies
31. ? SLE/autoimmune disorders
COPD = chronic obstructive pulmonary disorder; SLE = systemic lupus erythematosus.
* Partial listing only.

TRANSPLANT IMMUNOLOGY:
Lymphocytes, particularly T lymphocytes (T cells), are instrumental in transplantation failure and are stimulated during rejection
donor’s major histocompatibility complex (MHC), a genetic region
on the SHORT ARM OF CHROMOSOME NUMBER 6

HLA Class I antigens are expressed on most nucleated cells and on red blood cells.
HLA Class II antigens are expressed only on antigen-presenting cells (APCs) that include macrophages, B cells, dendritic cells, and some endothelial cells.

TYPE OF REJECTION DESCRIPTION
Acute Usually occurs within days to weeks due to primary activation of the T-cell response

Chronic Usually occurs months to years after transplantation; probably occurs by continued, albeit muted, cellmediated toxicity and other unclear causes

Hyperacute Usually occurs minutes to hours after transplantation and is caused by preformed antidonor antibodies activating complement

MEDICAL MANAGEMENT
focuses on successfully preventing rejection.
Blood and Tissue Typing
typing is mandatory in allogeneic HCT
DNA-based testing for tissue typing is being used more commonly today. Polymerase chain reaction (PCR) is used to identify the DNA in the HLA genes of both the donor and recipient cells

IMMUNOSUPPRESSION

CYCLOSPORINE
Macrolide immunosuppresant Prophylaxis against organ rejection Hepatotoxicity Immunosuppressant‡
Calcineurin inhibitor Nephrotoxicity P-450 metabolized§
Elevation of blood pressure
Gingival hyperplasiaMonitor CV systemMay effect renal elimination of some drugsRisk of neoplasm

TACROLIMUS
Macrolide immunosuppressant Prophylaxis against organ rejection Hepatotoxicity Immunosuppressant‡
Calcineurin inhibitor
Neurotoxicity P-450 metabolized§
Nephrotoxicity Monitor CV systemPost-transplant diabetes mellitus May effect renal elimination of some drugsElevation of blood pressure Risk of neoplasm

SIROLIMUS
1. Macrolide immunosuppressant Prophylaxis against acute and perhaps Hyperlipidemia Immunosuppressant‡
2. chronic organ rejection Hypertriglyceremia
3. P-450 metabolized§
4. Monitor CV systemMay effect renal elimination of some drugsRisk of neoplasm

AZATHIOPRINE
1. Antimetabolite Prophylaxis against organ rejection
2. Bone marrow suppression Immunosuppressant ‡
3. Hepatotoxicity Risk of neoplasm

MYCOPHENOLATE MOFETIL ANTIMETABOLITE
1. Prophylaxis against organ rejection and Leukopenia Immunosuppressant‡
2. possible agent to reverse ongoing Absorption is altered by antibiotics, antacids,
3. acute rejection and bile acid binders
4. Risk of neoplasm
5. ATG/ALG Polyclonal antibody Conditioning agents used prior to transplant Leukopenia Immunosuppressant‡
6. Pulmonary edemaRenal dysfunction

Muromonab-Cd3
1. Monoclonal antibody Reversal of acute organ rejection, including Cytokine release syndrome Immunosuppressant‡
2. steroid-resistant acute rejection Interacts with indomethacinDaclizumab and basiliximab Monoclonal antibodies Reversal of acute organ rejection Pulmonary edema Immunosuppressant‡
3. Renal dysfunction Risk of neoplasm

CORTICOSTEROIDS
1. Nonspecific immunosupressant Reversal of acute organ rejection Multiple# Broad nonspecific immunosuppressant‡
2. Avoid NSAIDs and ASAMonitor CV systemPoor wound healingRisk of neoplasmSteroid supplement may be needed withstressful procedures
3. Corticosteroids are consistently used in all allogeneic ransplantations for prophylaxis against graft rejection and for reversal of acute rejection

ASA = acetylsalicylic acid; ATG/ALG = antithymocyte globulin/antilymphocyte globulin; CV = cardiovascular; NSAIDs = nonsteroidal anti-inflammatory drugs.
‡Use of an immunosuppressant results in an increased risk of infection.
§Dental/oral pharmacotherapeutics that are metabolized by the liver’s cytochrome P450 3A system alter this drug’s serum levels. This group of medications includes, but is not limited to, erythromycin, clarithromycin, “azole” antifungals, benzodiazepines, carbamazepine, colchicines,, prednisolone, and metronidazole.

ANTITHYMOCYTE AND ANTILYMPHOCYTE GLOBULIN
medications may include sulfamethoxazole/trimethoprim, nystatin, fluconazole, acyclovir, ganciclovir, and others

OTHER CYTOTOXIC AGENTS
specifically busulfan and/or cyclophosphamide, and also total body irradiation.

NEWER IMMUNOSUPPRESSIVE STRATEGIES
1. The definitive immunosuppressive agent would be an agent that is able to destroy only the T cells that are involved with graft rejection, while leaving the remainder of the T cells and the immune system intact.
2. FTY720 is a new immunosuppressive compound that may cause antigen-induced apoptosis (programmed cell death)of cytotoxic T cells
3. Antimicrobial Medication
4. In addition to immunosuppressive medication regimens, antimicrobial medication regimens are important in preventing infection in the transplant recipient

DACLIZUMAB AND BASILIXIMAB
Daclizumab and Basiliximab are newer agents (synthetic monoclonal antibodies) used for reversal of acute organ rejection

[Part 2 will follow... soon]



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