Transplantation Flashcards
Define
a) autologous
b) syngenic
c) allogenic
d) xenogenic
a) transplant from a different part of the body of the same individual
b) transplant from a twin of the individual
c) transplant from a different individual
d) transplant from a different species
Describe hyperacute rejection
Occurs if there are pre-existing antibodies. A common example of this is the rejection of ABO mis-matched red cells (in a blood transfusion), causes type II hypersensitivity. Additionally, antibodies can form against MHC molecules: i) from a previous organ transplant ii) from pregnancy (at childbirth fetal cells enter maternal circulation and stimulate adaptive response to paternal MHC) iii) from blood transfusion matchesd for ABO but not MHC (a transplant must include nucleated cells, not just erythrocytes that lack MHC)
Hyperacute rejection also takes place in xenotransplants, which is a problem for companies hoping to use pigs as a source of organs for humman recipients. Natural antibodies recognise differently glycosylated proteins, and complement-regulatory proteins work less efficiently across the species barrier
Allogenic transplants and T cell memory response
Memory T cells are produced alongside effector T cells in a primary immune response. Upon a second exposure to the same antigens, memory T cells promote a more rapid, more effective response. This is because memory T cells to a specific antigen are more numerous than naive T cells and are more readily activated
Acute rejection
a) Direct recognition of allo-MHC
b) Indirect recognition
a) TCRs can bind strongly to multiple allogenic MHCs, even if they present self peptides. There is no central tolerance against all MHC. Normally, only a few MHC molecules on the cells would present a foreign peptide, but on the allogenic cell, every MHC molecule is a target, hence increased valency. Both CD8+ and CD4+ T cells mediate graft rejection
b) Some peptides are called minor histocompatibility (H) antigens. Female recipients of a male organ may generate immune responses against peptides encoded by genes on the Y chromosome (as there was negative selection of H-Y TCR). Rejection of minor H antigens is slower than rejection by direct recognition of MHC
Chronic rejection
Can occur several years after the initial transplant. The mechanism is poorly understood and may not always be immunological. May involve immune complexes that deposit on the vasculature supplying the graft - chronic allograft vasculopathy (a type III hypersensitivity)
a) Particular transplant situations (3)
b) Considerations of solid transplants
c) Haematopoietic transplants (when needed and additional dangers)
a) i) Transplant into privileged site (eg cornea) - no rejection, probably due to no lymphatic drainage
ii) Vascularised (solid) organs - kidney, liver, lung, heart
iii) Haematopoietic stem cell transplants
b) HLA matching (HLA-A, -B, -C, and -D are the most important to match), achieved by tissue typing (mAbs against the different MHC alleles would cause rejection) - genetic screening is used (sequencing) and also detection of pre-formed antibodies against MHC. Detection of pre-formed antibodies is achieved by cross-matching (see image)
a) Over 2000 people in UK need each year i) to correct inborn errors ii) to reconstitute the immune system after chemotherapy/irradiation (especially for leukaemia/lymphoma). Source is peripheral blood cells, bone marrow, cord blood.
Additional danger - graft bersus host disease (GvHD) - donor T cells attack host tissue. Also graft versus leukaemia (GvL) - takes place in infused donor CD8 T cells and NK cells kill remaining host leukaemic cells
Autologous transplantation - Adoptive cell therapy
Another form of cancer immunotherapy. T cells are removed from a tumour, expanded in vitro (in the presence of IL-2), assayed for any specific tumour recognition. Selected and expanded of the specific T cells and reinfused back into the patient
Therapeutics for transplantation
The most commonly used drugs to prevent transplant rejection are cyclosporine and rapamycin. Both of these interfere with signals generated by the TCR. Rapamycin also blocks IL-2 signalling. CTLA4-Ig is increasingly used for kidney transplantation (blocks CD28 costimulation). The transfusion of Treg cells is being evaluated as a possible mechanism of inducing tolerance to transplants.
