11 - MAb in Transplantation Flashcards
1
Q
Define transplantation
A
To transfer an organ or tissue from one part or individual to another
2
Q
Define autotransplantation
A
Transplantation of organs, tissues, or particular proteins from one part of the body to another in the same person
3
Q
Define allotransplantation
A
- Transplantation of cells, tissues, or organs to a recipient from a genetically non-identical donor of the same species
- Most human tissue and organ transplants are allografts
4
Q
Define xenotransplantation
A
Transplantation of living cells, tissues or organs from one species to another
5
Q
Types of donors
A
- Heart beating donor
- Non-heart beating donor
- Living donor
6
Q
Describe transplant rejection
A
- When the immune system of the host detects the transplant as foreign graft tissue, it launches an attack and results in tissue rejection
- Ultimate goal of transplant rejection tx = immune tolerance (state in which the host immune system recognized the foreign tissue but doesn’t react to it)
- Adaptive immune response
- Involves cellular immunity (killer T cells) and humoral immunity (B cells)
- Action is joined by components of innate immune response (phagocytes and soluble immune proteins)
- Different types of transplanted tissues tend to favour different balances of rejection mechanisms
7
Q
How does major histocompatibility complex (MHC) affect transplantation?
A
- MHC classes 1 and 2
- Number of mismatched gene alleles encoding MHC correlates w/ rapidity and severity of transplant rejection
8
Q
MHC matching
A
- Match HLA antigen between donor and recipient
- Most critical = matching at HLA-DR locus
- HLA-A and HLA-B are of less importance
9
Q
ABO-incompatible transplant (ABOi)
A
- Children under 12 months or as old as 24 months
- Don’t have well developed immune system, so possible for them to receive organs from otherwise incompatible donors
- Graft survival and pt mortality is about the same between ABOi and ABO-compatible (ABOc) recipients
10
Q
Describe immunological mechanism of rejection (minus humoral immunity)
A
- Immunization
- Immune memory – memory helper T cell’s receptor (CD4 receptor) recognizes antigen presented by MHC class 2 molecules; immune memory is pro-inflammatory
- Cellular immunity – cytotoxic T lymphocytes T cell receptor (CD8 receptor) recognizes antigen presented by MHC class 1 molecules; trigger target cell’s programmed cell death by apoptosis
11
Q
Describe humoral immunological mechanism of rejection
A
- Antibody dependent cytotoxicity
- Opsonization (IgG’s Fc region can enable opsonization by a phagocyte through the Fc receptor on the phagocyte)
- Complement dependent cytotoxicity (conformational shifts of IgG’s Fc region can host a complement protein to initiate the complement cascade)
12
Q
Hyperacute rejection
A
- Immediate (w/in minutes) and rare
- Initiated by pre-existing humoral immunity w/ complement activation
- After transplant, blood circulation returns and antibody binds to the grafted tissue, which activates the inflammatory response and the coagulation cascade
- Results in clot formation in blood vessels to new tissue
- Likely outcome of xenotransplant
13
Q
Acute rejection
A
- Developing w/ formation of cellular immunity (mononuclear macrophages and T-lymphocytes)
- Usually begins 1 week after transplantation (highest in the first 3 months)
- Single episode isn’t a cause for concern if recognized and treated promptly; rarely leads to organ failure
- Recurrent episodes lead to chronic rejection, which can’t be treated
- Immunosuppressive drugs are effective
- Th cell activation takes 2 weeks
14
Q
Chronic rejection
A
- Long-term loss of function in transplanted organs via fibrosis of the transplanted tissue’s blood vessels (chronic allograft vasculopathy)
- Irreversible but tissue typing and immunosuppressive drugs may decrease likelihood of chronic rejection
- If rejection can’t be managed, another transplant may be necessary
- Due to memory and specificity of the immune system, subsequent rejections occur even more quickly and vigorously
15
Q
Mechanism of different transplant rejections
A
- Blood = antibodies
- Kidney and heart = antibodies and cell-mediated
- Skin and bone marrow = cell-mediated
- Cornea = usually accepted as cell-mediated unless vascularized
16
Q
Graft vs. host disease (GVHD)
A
- Not only host immune system can attack donor organ
- Lymphocytes from donor are carried by the organ into the body of the recipient (host)
- If recipient is immunocompromised, foreign lymphocytes can attack recipient tissue => skin rashes, intestinal problems, organ failure, death
- Liver, spleen, and bone marrow transplants carry high risk of GVHD
17
Q
Hyperacute rejection tx
A
- Usually manifests severely and w/in minutes
- Immediate tx is removal of the tissue
18
Q
Chronic rejection tx
A
- Generally considered irreversible and poorly amenable to tx
- Tx = retransplant if feasible
19
Q
Immunosuppressive drug options for transplantation
A
- Corticosteroids – prednisolone, hydrocortisone
- Calcineurin inhibitors – cyclosporine, tacrolimus
- Anti-proliferatives – azathioprine, mycophenolic acid
- mTOR inhibitors – sirolimus, everolimus
20
Q
Why do we need MAb in solid organ transplantation?
A
- Available agents associated w/ significant pt and allograft adverse effects
- Leading cause of death in non-cardiac transplant recipients is a CV event linked to long-term corticosteroid exposure
- Chronic administration of calcineurin inhibitors (cyclosporine and tacrolimus) associated w/ acute and chronic kidney dysfunction
21
Q
Antibody drugs for transplantation
A
- Monoclonal anti-IL-2R alpha receptor antibodies – basiliximab, daclizumab
- Monoclonal anti-CD52 antibody – alemtuzumab
- Monoclonal anti-CD20 antibody – rituximab
- Monoclonal anti-C5 antibody – eculizumab
- Polyclonal anti-T-cells antibodies – rabbit anti-thymocyte globulin (ATG) and rabbit anti-lymphocyte globulin (ALG)
22
Q
Application of Ab in transplantation (when can they be given)
A
- Pre-transplant -> decrease inherent immune-reactivity of the potential transplant recipient prior to engraftment
- During transplant -> induce global immunosuppression at the time of transplantation allowing modified intro of other immunosuppressive agents (calcineurin inhibitors or corticosteroids)
- After transplant -> sparse exposure to maintenance immunosuppressive agents
23
Q
MAb administered pre-transplant **know this
A
- Used to desensitize recipient’s immune system
- Desensitization = immunosuppression administered prior to transplant to prevent hyperacute or early rejection in px who are known to have circulating antibodies (anti-A or anti-B) against human antigen
- Reserved for px who are “highly sensitized” during transplant evaluation
- Rituximab**
24
Q
MAb administered at time of transplant
A
- Called induction
- Decreases need for corticosteroids and allows for delay or reduction in amount of calcineurin inhibitor used
- Determination of the recipient’s immunologic risk at the time of transplant should be done to determine which MAb to use in order to minimize the risk of early acute rejection and graft loss
- To minimize high risk for acute rejection or to maintain immunosuppression, use:
- Polyclonal antibody (ATG, ALG)
- Monoclonal antibody (alemtuzumab, daclizumab, basiliximab)
25
MAb administered following transplant
- Used to treat allograft rejection (mainly reserved for severe allograft rejection)
- Eculizumab**
- Cautions -> interruption of immune systems (humoral or cellular) through the use of MAb places these px at significant risk for infection and malignancy
26
Compare and contrast daclizumab, basiliximab, and alemtuzumab
- Daclizumab and alemtuzumab = humanized; basiliximab = chimeric
- Daclizumab and basiliximab target = CD25 alpha subunit; alemtuzumab = CD52
- Daclizumab and basiliximab target IL-2 dependent T-lymphocytes
- Target of alemtuzumab = peripheral blood lymphocytes, NK cells, monocytes, macrophages, and thymocytes
- All used at time of transplant (induction)
27
Rituximab -- type, molecular target, target cells, and use
- Chimeric
- CD20
- Targets B-lymphocytes
- Used for desensitization Ab mediated rejection (pre-transplant)
28
Eculizumab -- type, molecular target, target cells, and use
- Humanized
- C5
- Targets T-lymphocytes
- Used for atypical hemolytic-uremic syndrome and Ab-mediated rejection (post-transplant)
29
Describe the relationship between T-cell receptors and IL-2
- Actual T-cell receptor is made up of 3 subunits – alpha (CD25, Tac), beta (CD122), and gamma (CD132)
- - Beta and gamma subunits can only be stimulated by high concentrations of IL-2
- - Alpha subunit shows high affinity for IL-2 and can be stimulated at very low concentrations of IL-2
- - IL-2 receptor (CD25) is only expressed on activated T-cells
- - Blockage of IL-2 bound to CD25 decreases proliferation and clonal expansion of T-cells
30
Daclizumab -- target, what levels in the blood produce an effect
- Humanized IgG1 against the alpha portion of the IL-2 receptor (CD25)
- First “humanized” MAb approved in US for human administration
- Serum concentration of 1 ug/mL is required for 50% inhibition of antigen induced T-cell proliferation
- 5 doses of 1 mg/kg given every other week to produce serum concentrations needed to achieve 90% inhibition of T-cell proliferation for 12 weeks
31
Daclizumab dosing
- Immunoprophylaxis -> 1 mg/kg infused over 15 minutes w/in 24 h before transplantation then q14days for 4 additional doses
- Tx of GVHD -> 0.5-1.5 mg/kg, repeat same dosage for transient response
32
Basiliximab -- target, serum concentrations to produce effect, dosing, and indications (what type of transplant)
- More potent IL-2 receptor antagonist than daclizumab
- Chimeric (murine/human) MAb directed against alpha subunit of IL-2 receptor (CD25) on surface of activated T-lymphocytes
- Complete inhibition of CD25 receptor occurs at serum concentrations > 0.2 mg/mL
- Currently, recommended dose = 20 mg administered 2 h prior to transplanted organ reperfusion and subsequent 20 mg dose on post-op day 4
- Now used in kidney, lung, liver, and pancreas transplant recipients
- Mainly used for px at low to moderate risk of acute rejection
33
Alemtuzumab -- target and indication
- Humanized MAb targeting cell surface glycoprotein CD52
| - Currently used for induction and tx of rejection in pancreas, intestinal, and liver transplant recipients
34
What is the CD20 cell surface protein?
- CD20 protein expressed on all B-cells, from pre-B-cells to activated B-cells; not on hematopoietic stem cells, plasma cells, and T-lymphocytes
- CD20 protein = calcium channel responsible for B-cell proliferation and differentiation
35
Eculizumab (Soliris) -- target and indication
- Humanized MAb that targets complement protein C5 (inhibits C5 cleavage into C5a and C5b, therefore preventing formation of membrane attack complex
- Used for prophylaxis as well as in renal transplantation post-transplant
