Transplantation and Immunosupressive Drugs Flashcards
what is transplantation?
the introduction of biological material (organs, tissue, cells) into an organism
what has the immune system evolved to do?
the immune system has evolved to remove anything it regards as non-self
why was the eye transplant so successful and done so early on?
because it’s an immunologically privileged site
Donor/recipient relationships - diff types?
Autologous
Syngeneic
Allogenic
Xenogenic
Autologous vs Syngeneic
for both of these, you wouldn’t expect an immune response
Autologous: Transplantation of tissue from 1 part of the organism into another part of the same organism. May be inflammatory responses, but no immune response as it is “self transplanting into self”
Syngeneic: Donor material transplanted into a recipient - donor and recipient are genetically identical.
Allogenic vs Xenogenic
both are genetically different, immune response may be generated
Allogenic: Donors and recipients are from the same species but genetically different
Xenogenic: Donor and recipient are different species
what are Immune responses to transplant caused by?
genetic differences between the donor and the recipient
- most important are differences between the antigens forming the major histocompatibility complex (MHC)
- MHC = biggest site of variability in human genome, which is why immune responses are raised against it
what is the human antigen called?
HLA (human leukocyte antigen)
HLA diversity
can be split into class I and class II:
Class I has 3 alleles
Class II are dimers and there are 6 alleles
Almost all mutated cells express HLA class I Only WBC’s/professional APC's express HLA class I and HLA class II – important for rejection
Importance of epitopes on donor MHC
there are B-cell epitopes on donor MHC, T-cell epitopes derived from donor MHC
1000’s of HLA alleles but perhaps only 100’s of epitopes - this means that even if people have different HLA’s, they may still have the same epitopes, therefore rejection won’t occur.
So, we are moving from matching recipient and donor HLA’s to matching recipient and donor alleles on the HLA, but NGS is too expensive for this to become a regular thing right now
what do T cells need to recognise?
foreign peptides bound to self-MHC
- peptide is bound into the binding groove
- TCR detects the combination of peptide and MHC
T cells and MHC class I
CD8 T cells recognise short peptide fragments from intracellular proteins that are presented to them by major histocompatibility (MHC) proteins
eg. a cell infected by a virus, viral proteins are processed by the proteasome into peptides
T cells and MHC class II
MHC class II only on WBC’s and professional APC’s
Good at taking up external material into a phagolysosome and breaking it down into peptides
Peptides interact with vesicle containing MHC
CLIP maintains the shape of HLA until the peptides are ready to bind.
MHC/peptide —-> APC surface, activates CD4 T cells
types of T cells?
Cytotoxic T cells – highly specific killer cells
Helper T cells – information and support for other immune cells via cytokine production
in transplants, what may be foreign?
In transplants, both the MHC protein and the peptide in its binding groove may be foreign
so, donor HLA could be detected as foreign by the recipient immune system, or the peptide, OR both!
Direct and indirect T-cell activation
Direct allo recognition = recipient TCRs detecting donor/non-self HLA
Indirect allo recognition = recipient TCRs detecting donor/non self peptides
Self HLA + self peptide = no T-cell activation
Self HLA + non self peptide = T-cell activation
Matched HLA + peptide = no T-cell activation
Unmatched HLA + peptide = T-cell activation
Live vs dead donors
Recipients will have a history of disease which will have resulted in a degree of inflammation
Organs from deceased donors are also likely to be in inflamed condition due to ischemia
Transplant success is less sensitive to MHC mismatch for live donors
Types of graft rejection
Hyperacute rejection
Acute rejection
Chronic rejection
Hyperacute rejection
Within a few hours of transplant
Most commonly seen for highly vascularised organs (e.g. kidney) because it is easier for an immune response to target highly vascularised tissue
Requires pre-existing antibodies, usually to ABO blood group antigens expressed on blood vessel endothelial cells, or to MHC class I - Antibodies to MHC can arise from pregnancy, blood transfusion or previous transplants
Antibodies bind to endothelial cells, complement fixation. Accumulation of innate immune cells, endothelial damage, platelets accumulate, thrombi develop
How can antibodies cause damage to transplanted tissue?
The pre existing antibodies detect their antigen on the donor tissue, bind via the Fab-like fragment (variable)
The Fc region on antibodies can bind to Fc receptors on immune cells, initiating a quick innate immune response.
Recognition of Fc region leads to complement activation:
- Antibody dependent cellular cytotoxicity
(Fc Receptors on NK cells) - Phagocytosis
(Fc Receptors on macrophages)
Acute rejection
Inflammation results in activation of organ’s resident dendritic cells (donor DC’s, NOT recipient)
T cell response develops as a result of MHC mismatch
Direct allorecognition of foreign MHC
eg. kidney transplant
inflammation activates recipient DC’s (in this case, they are in the kidney)
DC’s migrate to secondary lymphoid tissue. They are professional APC’s so they have MHC class I/II. Activate effector CD4 and CD8 T cells, which proliferate and migrate to the donor organ.
CD4’s and CD8’s target every cell that expresses the “foreign” HLA in the tissue and destroy the kidney transplant.
Chronic rejection
results from indirect allorecognition of foreign MHC/HLA
Donor-derived cells die, and cells taken up and broken down by host DC’s and presented as peptides on host MHC. DC’s activate T cells in the lymph node, which are sensitive to the foreign peptide and kill any cell presenting it.
Can occur months or years after transplant - this MHC mismatch effect is less pronounced so takes longer to develop.
Blood vessel walls thickened, lumina narrowed – loss of blood supply
Haematopoietic Stem cell transfer (HSCT)
The donor immune response is removed, and the stem cell transfer provides a new immune system
HSCs can find their way to bone marrow after infusion and regenerate there
They can be cryopreserved with little damage
Graft Versus Host Disease
When transplanted tissue is immune cells themselves, there is the risk of donor immune cells attacking the host – GVHD
Can be lethal – best approach is prevention
Removing T cells from transplant or suppressing their function reduces GVHD
Graft versus Leukemia
But sometimes mismatch and donor leukocytes can be benificial - removing original leukemia
Graft versus leukemia response
Development of GVL may prevent disease relapse
Typically happens with radiation therapy with leukaemia, where the patients immune system is destroyed, so they need a transplant of immune cells
There could be residual tumerogenic cells – but the new immune cells can target it in a way that the host immune system cannot – why? It’s because the cancer cells are self, so the immune system struggles to recognise it, so adding in these donor immune cells and creating a whole new immune system is a benefit.
Immunosuppression
Essential to maintain non-autologous transplant, even if there’s good HLA matching
Immunosuppressants for transplant can be -
General immune inhibitors (e.g. corticosteroids)
Cytotoxic – kill proliferating lymphocytes (e.g. mycophenolic acid, cyclophosphamide, methotrexate)
Inhibit T-cell activation (cyclosporin, tacrolimus, rapamycin)
Immunosuppressives may need to be maintained indefinitely
autologous transplant
uses a person’s own stem cells
Cyclosporin
Breakthrough drug for transplant
Blocks T cell proliferation and differentiation, Inhibit production of IL-2
Next generation therapies less toxic and effective at lower doses
Combination immunosuppressive regimes
(1) Steroids – e.g. prednisolone
(2) Cytotoxic – e.g. mycophenolate motefil
(3) Immunosuppressive specific for T cells – e.g. cyclosporin A,
Combination is typically more effective than single drugs, and it may also allow you to lower the dose of them and reduce side effects
Immunosuppressive therapy monitoring
There is currently no immunosuppressive that will prevent transplant rejection whilst maintaining other immune responses
Transplant patients more susceptible to infection and malignancy
Immediate risk e.g. CMV
Immunosuppressive drug toxicity can lead to organ failure eg cyclosporin nephrotoxicity in kidney transplant.
Needs to be monitored as an immune response against the transplant may happen quietly in the background
Intestinal microbiome
The microbiome, particularly of the intestine, is involved in regulating adaptive immune responses
-releases metabolites that reduce or increase the functioning of the immune system in a general way
Immunosuppressed/cancer patients who don’t respond to immunotherapy can take FMT (faecal material transplant) and it allows them to start responding – positive treatment effect.
May be implicated in transplantation outcomes
