Transplantation and immunology Flashcards
1
Q
Definitions of transplant relationships
A
- Autologous: self
- Syngenic: identical twin or clone
- Allogenic: non-identical (matched related or unrelated, cord blood, haploidentical)
2
Q
3 types of transplant rejection
A
- Hyperacute (first couple days): preformed Abs bind to graft and cause complement activation, leading to damage and thrombosis of vessels within the graft
- Acute (cellular or Ab mediated)
- Ab mediated: 3 types, all involve circulating Abs that activate complement (Cd4), can be arterial or capillary involvement (can be w/ or w/o inflammation)
- T cell mediated: 5 types, all result in inflammation of the vessels w/in the transplanted organ, this leads to fibrosis of the vessels
- Chronic: the 5th type of T cell mediated rejection, with continual inflammation and fibrosis
3
Q
How to prevent rejection
A
- Closely match donor and recipient
- Removed preformed Abs from recipient to prevent hyper acute rejection
- Block co-stimulatory molecules (CD28)
- Immunosuppressive medications
4
Q
Complications of immunosuppressive drugs
A
- Infections, malignancies
- Viral infections: CMV, EBV, PTLD (post transplant lymphoproliferative disease), BK virus
- BK virus: immunosuppression leads to reactivation (80% have the virus), BKV nephropathy is responsible for at least 50% of graft loss
- Other infections: fungal, bacterial
- Malignancies: EBV lymphoproliferative disease, kaposi’s sarcoma, squamous cell CA
5
Q
Cell types involved in alloreactivity
A
- Passenger leukocytes: MHCII bearing donor Ags w/in the graft
- Alloreactive helper T lymphocytes: recipient CD4 lymphocytes that recruit and activate macs
- Alloreactive CTLs: recipient CD8 Ts that lyse graft cells
- B lymphocytes: donor derived B lymphocytes that produce alloAbs and bind to graft endothelium
6
Q
Immunosuppression (IS) regimens
A
- Induction: basiliximab and anti-thymocyte globulin
- Maintenance: steroids, tacrolimus or cyclosporin, MMF or azathioprine, sirolumus, rituximab
- Side effects of IS: non immune toxicity to other tissue, consequence of IS for infection and malignancy
7
Q
Basiliximab
A
- Anti-CD25 monoclonal Ab
- Used in patients w/ low-moderate risk of rejection
- Expression of CD25 requires T cell activation
- CD25 is IL2 binding site, blocking this prevents further activation and proliferation of T cells
- Causes little depletion and has minimal toxic effects
8
Q
Antithymocyte globulin (ATG)
A
- Monoclonal IgG from other species, directed against T cells
- Provides a profound and durable lymphopenia
- May cause thrombocytopenia, cytokine release syndrome, serum sickness (type III hypersensitivity), allergic rxn
9
Q
Cyclosporin
A
- Binds to cyclophilin, which binds to calcimodulin and calcineurin to form a complex of all 4
- This prevents initial activation of T cell via TCR signaling pathway
- Side effects (dose-dependent): nephrotoxicity, HTN, hyperlipidemia, gingival hyperplasia, hirsutism (excessive hair), tremors
- May cause diabetes, hemolytic-uremic syndrome
- Monitor levels
10
Q
Tacrolimus
A
- Binds to FK506 which complexes w/ and inhibits calcineurin (greater potency than cyclosporin)
- Side effects similar to cyclosporin, but less likely to cause hyperlipidemia, HT, or hirsutism
- More likely to cause diabetes
- Monitor levels
11
Q
Mycophenolate mofetil (MMF)
A
- Inhibits monophosphate dehydrogenase (purine synthesis)
- Side effects: GI (diarrhea) and hematologic (leukopenia, anemia)
12
Q
Sirolumus
A
- Binds to NFKB12 and then inhibits mTOR (blocking signal 3 transduction, from CD25 activation by IL2)
- Side effects: hyperlipidemia, thrombocytopenia, bleeding, proteinuria, pneumonitis
- May decrease the risk of some viral infections (CMV) and neoplasms
13
Q
Rituximab
A
- Monoclonal Ab that binds to CD20 located on B cells (but not plasma cells)
- B cells may be acting as APCs against the graft
- May have long-term effects and risks
14
Q
Hematopoietic stem cell (HSC) transplant
A
- Source of HSCs can be BM, peripheral blood, or cord blood
- Same rules apply for organ Tx (autologous, syngenic, or allogenic)
15
Q
Indications for allogenic HSC Tx
A
- Hematologic malignancies (myeloid and lymphoid): eliminated malignant cells w/ high dose chemo and provide graft-vs-disease (GvD) effect
- BM failure: replace HSCs (aplastic anemia)
- Inherited genetic disease (SCID, SCD): correct genetic defect in cells that originate from HSCs
- Immunodeficiency and autoimmune disease (lupus): reconstitute new immune system
16
Q
HSC (CD34+) mobilization
A
- HSCs are kept in BM by various proteins binding to BM tissue, namely CXCR4 binding to CXCL12 (SDF1)
- CXCR4 is on the HSC and CXCL12 is released from the niche osteoblast to keep the HSC attached w/in the BM
- Administering GCSF leads to release of proteases by neutrophils that breaks down both CXCL12 and part of CXCR4
- This leads to detachment of the HSCs from the BM and their entry into peripheral circulation
17
Q
Passenger cells
A
- CD34+ cells from BM are donated along w/ other cells that reside in peripheral blood
- Some of these are CD3+ mature, naive T cells, which are responsible for GvHD (were educated in donor’s thymus)
- However the donated CD34+ HSCs will mature into lymphocytes in the recipients body
- This means the T cells and B cells from the donor HSCs will be educated in the recipient’s thymus and BM, respectively. They will contribute to GvD phenomenon (will not self-react)
18
Q
Types of HSC grafts
A
- BM aspirates contain high amounts of HSCs, w/ moderate PMNs and platelet recovery time, and a moderate GvHD risk
- Blood stem cells (form GCSF mobilization) contain high amounts of HSCs, w/ low PMNs and platelet recovery time, and a high GvHD risk
- Cord (placental) blood have low HSC content and higher PMN and platelet recovery time, but lowest GvHD risk
19
Q
Graft vs host disease (GvHD) 1
A
- Donor T cell recognition of genetically disparate recipient who is unable to reject the donor cells
- Donor T cell recognition of host Ags in context of host APCs
- Risk factors: HLA match is biggest (closer the HLA match the better the outcome), also age, sex match, graft source (higher to lower risk: PBSC>BM>cord blood), allosensitization of donor, conditioning intensity
20
Q
Graft vs host disease (GvHD) 2
A
- Acute: affects skin, liver, GI (usually onset 15-30 days after Tx)
- Maculopapular rash, cholestasis, high AST/ALT, nausea, vomiting, diarrhea
- Chronic: multisystem disease that resembles autoimmune disorders
21
Q
Acute GvHD pathogenesis
A
- Priming of immune response from conditioning (immunosuppressive chemoRx), pro inflammatory cytokines, activation of APCs
- Induction of T cell activation: recognition by donor T cells of host Ags on APCs in secondary lymphoid tissues, leading to expansion of reactive donor T cells
- Homing of cells to target tissues: mediated by adhesion molecules and chemokines
- Effector phase: destruction of target tissues via cell surface molecules and soluble immune effector molecules
22
Q
Minor histocompatibility Ags
A
- Peptides derived from polymorphic proteins that differ btwn donor and recipient
- Initiate weaker immune responses than major Ags
- Mediate graft vs disease effect (beneficial)
- In HSC Tx btwn male and female donor/recipient genes on Y chromosome act as minor histocompatibility Ags
23
Q
Graft vs disease effect
A
- Contributes to cure of malignant disease
- Mediated by expression of tumor Ags, minor and major HLAs on malignant cells
- Extent of effect varies depending on disease: CML>AML>ALL
- Basis for donor lymphocyte infusions
24
Q
Prevention of GvHD
A
- Post transplant immunosuppression: calcineurin inhibitor (cyclosporine or tacrolimus) w/ another chemo agent (methotrexate or mycophenolate)
- In vitro or in vivo T cell depletion of graft: use of Abs to target donor T cells (ATG), this increases risk for infection
25
Q
Complications of allogenic HSC Tx
A
- Regimen related toxicity
- Engraftment failure
- Infections (due to neutropenia, catheters, mucosal damage from conditioning and GvHD, steroid and impaired cellular and humoral immunity)
- Impaired cellular immunity due to immunosuppression and acute GvHD
- Impaired humoral immunity due to chronic GvHD
- GvHD (acute and chronic)
- Late effects
26
Q
Viral infections after HSC Tx
A
- CMV: reactivates upon immune suppression. Seronegative recipients receiving seropositive donor cells are at increased risk (monitored by PCR after HSC Tx)
- EBV
- HSV
- VZV
- HHV6
- BKV
- Respiratory viruses
27
Q
Fungal infections after HSC Tx
A
- Candida
- Aspergillus
- Other mycoses
- Pneumocytis Jiroveci
28
Q
Conditioning regimen-related toxicity
A
- Hepatic venocclusive disease: jaundice, fluid retention, tenderhepatomegaly, endothelial injury by toxic drug metabolites
- Idiopathic pneumonia (absence of infectious pathology)
- Diffuse alveolar hemorrhage
- Mucositis
- Hemorrhagic cystitis
29
Q
In utero HSC Tx for SCID
A
- IL2RG receptor mutation identified at 12 wks gestation
- Results in T cell depleted prenatal BM
- Inject HSC into peritoneal cavity 3x
- Persistent engraftment of donor T cells that were responsive to mitogens and tolerant to recipient
