Direct and Indirect Alloantigen Recognition

00:01 Rejection can be due either to a direct or an indirect alloantigen recognition.

00:11 In direct alloantigen recognition, the allogeneic antigen presenting cell in the graft shows the allogeneic MHC to a alloreactive T-cell.

00:29 The T-cell in the recipient recognizes unprocessed allogeneic MHC molecules on the graft APC.

00:38 So the graft from the donor will most often have some foreign MHC molecules.

00:47 It’s almost impossible to completely match between the donor and the recipient across all of the MHC molecules.

00:55 Remember there will be six different MHC Class I’s, six different MHC Class II’s.

01:03 So matching perfectly is incredibly difficult and incredibly rare.

01:09 So usually there will be this recognition of allogeneic MHC, and here we see it occurring in a direct way where the recipient’s T-cells directly recognize the foreign MHC on the donor cells.

01:26 There is also indirect alloantigen presentation which occurs.

01:33 This is due to uptake and processing of the allogeneic MHC molecules by the recipient’s antigen presenting cells.

01:44 And peptides derived from the allogeneic MHC molecule are shown to the T-cells in the recipient.

01:52 So there is presentation of processed peptide of the foreign allogeneic MHC molecule bound to the recipient’s own self MHC molecules.

02:04 So fragments of the foreign MHC being shown by the recipient’s MHC to the T-cell receptor on their T-cells.

02:14 And both of these processes take place following transplantation unless there is an absolutely perfect match.

02:22 Let us now look at the activation of alloreactive T-cells.

02:27 There will be a sensitization phase, where the donor dendritic cells and recipient dendritic cells will show donor alloantigen to T-cells.

02:42 There’ll be transport of those alloantigens to the lymph nodes with activation of T-cells.

02:49 The generation of effector T-cells in the recipient by both the direct and indirect antigen presentation pathways that we’ve just explored.

03:01 And both recipient CD4 T-cells and recipient CD8 T-cells will become activated.

03:11 Those recipient effector T-cells can then migrate to the allograft.

03:18 And there will be activation of the effector T-cells by alloantigens, by foreign antigens from the donor tissue.

03:27 And this can result in graft rejection with killing of target cells and cytokine secretion.

03:36 Let’s have a look in a little bit more detail at the precise events in the immunological rejection of a graft.

03:44 And we’re going to use a liver graft as an example.

03:47 So there’ll be both donor and recipient antigen presenting cells.

03:51 And in the presence of co-stimuli, Th0 cells can be differentiated into other populations of T-cells.

04:00 These will include T-regulatory T-cells that can be produced, and would actually be beneficial in preventing the rejection of the graft.

04:11 But the balance overall is towards the generation of T-cells that contribute towards graft rejection.

04:18 In the presence of interleukin-12, Th0 cells will differentiate into Th1 cells.

04:26 These Th1 cells produce gamma interferon which cause the upregulation of MHC Class I and MHC Class II molecules on the donor cells.

04:38 Interleukin-2 is also produced by Th1 cells, which will cause the activation of cytotoxic T-lymphocytes, which can recognize peptides presented by the MHC Class I molecules.

04:51 Gamma interferon from Th1 cells will cause activation of macrophages with the secretion of the cytokines IL-1 and TNF-α.

05:04 These cytokines are pro-inflammatory and will contribute towards the rejection process.

05:10 Interleukin-4 will cause Th0 cells to differentiate into Th2 cells which secrete interleukin-4, interleukin-10 and interleukin-13.

05:23 These help activate B-cells to differentiate into plasma cells and to secrete antibodies.

05:31 Natural killer cells can then recognize the antibody coated donor cells, and mediate ADCC (antibody dependant cellular cytotoxicity).

05:45 Complement can also bind to these antibodies and become activated via the classical pathway, and again contribute towards the graft rejection.

05:56 Here we can see the acute rejection in a heart transplant recipient.

06:01 There is a cellular infiltrate of both lymphocytes and macrophages.