Case 14: Transplant Flashcards
Lymphocyte patterns in immunodeficiency 1
- Primary or secondary immunodeficiency: Lymphopenia
- SCID: low T cells +/- B cell and NK cell lymphopaenia
- Infection, malignancy, drugs: low CD4+
- Secondary agammaglobulinemia: absent B cells
- Viral infection, leukaemia and lymphoma: Lymphocytosis
Lymphocyte patterns in immunodeficiency 2
- CGD: defective neutrophil function
- Haemophagocytic Lymphohistiocytosis (HLH): defects in NK cell and cytotoxic T cell function
- Lymphoproliferative disease: isolated low IgM
- Liver disease: high IgM
- Chronic infection and inflammation: raised polyclonal IgA (also seen in elderly)
- Sjogrens syndrome and HIV: raised IgG
HLH
A life threatening Immunodeficiency of severe hyperinflammation due to uncontrolled proliferation of activated lymphocytes and histiocytes.
Paraprotein
A marker of plasma cell disorder such as multiple myeloma. Investigated with serum electrophoresis. Its the immunoglobulin product of a single cell clone. Confirmed with Immunofixation
Pre Transplantation tests
- Hep B sAg, Hep B sAb, HIV Ag/Ab, Hep C Ab, CMV IgG and IgM
- ABO blood group
- HLA typing: HLA-DR, HLA-A and HLA-B. Preferable are: HLA-C, HLA-DP and HLA-DQ
- Anti-HLA antibody serology
- Cross match: T cell crossmatch is a contraindication to transplant. If antibody detected in host, then should undergo plasmapheresis pre-transplant.
Transplantation: common definitions
- Transplantation: The transfer (engraftment) of human cells, tissues or organs from a donor to a recipient with the aim of restoring function(s) in the body
- Graft – The transplanted tissue
- Donor – The source of the graft
- Recipient – The individual receiving the transplant
- Allo (as in “allograft”) – from a genetically different member of the same species
Transplantation: use and epidemiology
- Solid organ transplants are used in: kidney, heart, liver, lung, pancreas or bowel disease
- Many people need repeat transplantation but demand for organs outstrips supply
- Half of lung transplants are lost in 5 years
Immune response to transplants
- Immune response in transplant are primarily: polymorphic HLA gene products i.e. MHC
- Other targets include AB blood group antigens and minor histocompatibility antigens
- Antigen-specific response directed by lymphocytes (B and T cells)
- Other factors in rejection: Innate immune cells, including NK cells, macrophages and neutrophils, as well as endothelial cells.
HLA- Human Leukocyte Antigen
- Major Histocompatibility Complex (MHC), genes involved in antigen processing and presentation on chromosome 6
- Class 1 (HLA-A, -B and -C) expressed on all cells as MHC-1 and present antigens to CD8 T cells
- Class II (HLA-DR, -DP and -DQ) expressed on APCs as MHC-2 and present antigen to CD4 T cells
Types of transplant rejection
- Hyperacute: minutes to hours, pre-existing antibodies (previous pregnancy, transfusion, transplantation etc)
- Acute: days to weeks, Cellular (T-cell mediated), Humoral (antibody production requiring T and B cell function)
- Chronic: months to years, complex aetiology
Hyperacute rejection
- Targets: blood group antigens and MHC molecules
- Rare due to screening and cross matching
- Rapid extensive thrombosis and graft infarct, usually needing graft removal
- Due to pre-existing anti-donor antibodies in the recipient
- Treatment is removal of organ
MoA of Hyperacute rejection
- Rapid binding of antibodies to graft antigens
- Activation of complement: Cell lysis, increased leucocyte recruitment / inflammation
- Endothelial activation, release of pro-thrombotic substances (e.g. Von Willebrand factor); Platelet aggregation, thrombosis, and occlusion of graft microvasculature
- Causes thrombosis and graft infarction usually needing graft removal
MoA acute rejection
- T cells recognise antigens on APC’s from the donor graft (direct) or on the recipients APC’s (indirect).
- When activated the APC express co-stimulatory molecules i.e. B7 which bind to receptors on T cells causing them to proliferate into effector cells.
- Need both the antigen and the co-stimulatory molecules to activate the T cell
Effects of T cells in acute rejection
- CD8 (cytotoxic) T cells infiltrate the graft recognise foreign MHC-1 and kill the cell
- CD4 Th(helper)1 effector cells: infiltrate the graft and recognise foreign MHC-2, causing the release of proinflammatory cytokines (IFN-Y, TNF) which recruit neutrophils and Macrophages causing tissue damage, altered vascular function and ischaemia
Effects of T cells in acute rejection: CD4 TH2 cells
CD4 TH2 effector cells recruit B cells to differentiate into plasma cells. Plasma cells produce antibodies targeting donor antigens (donor specific antibodies - DSAs). Circulating DSAs bind to graft endothelial cells, activate complement, endothelial cell damage, microvascular thrombosis in graft
Antibody mediated acute rejection
- Antibodies to donor antigens bind to antigens on endothelial cells.
- This leads to complement activation leading to formation of MAC pores and inflammatory cell recruitment.
- This leads to inflammation and complement-mediated cell lysis results in graft damage and microvascular thrombosis.
Acute rejection: Diagnosis
- Presentation: acute deterioration in graft function (rise in creatinine and decreased urine output in renal, deranged LFTs in liver, cardiac failure in heart etc.). Pain and graft oedema
- Screening for rejection routinely: U&Es, urinalysis in kidney, LFTs in liver, PFTs in lung, echo in heart etc
- Gold standard: biopsy with histological findings
- Serological test: identify donor specific antibodies
Acute cellular rejection (ACR) vs Acute antibody mediated rejection (AMR) biopsy findings
Acute cellular rejection (ACR) biopsy findings: diffuse cellular infiltrate and lack of complement C4d staining. Dense lymphocytic infiltration
Acute antibody mediated rejection (AMR) biopsy findings: Mononuclear cells (lymphocytes/monocytes) infiltration. C4d deposition.
Difference between ACR and AMR: complement is activated in AMR
Treatment of cellular rejection (T cell mediated)
- No antibodies or complement
- Treated with increased immunosuppression
- High dose puled IV methylprednisolone 500mg daily for 3 doses
- With or without T cell depleting therapy, depending on severity: Anti-thymocyte globulin (ATG)
- Usually responds well to treatment
Treatment of antibody mediated rejection
- Potent immunosuppression to remove donor specific antibodies (DSA)
- Methylprednisolone IV 500 mg daily for 3 days
- Plasma exchange (plasmapheresis) - to directly remove DSAs
- High dose (immunomodulatory dose) IV immunoglobulin
- Anti-B cell agents: Bortezomib (proteasome inhibitor – depletes plasma cells), or Rituximab (anti-CD20, B cell-depleting agent)
- Other immunosuppression continued as standard
- Infection prophylaxis with antibiotics and anti-virals including co-trimoxazole and valganciclovir
- Responds less well than cellular rejection