Direct and Indirect Alloantigen Recognition

by Peter Delves, PhD

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    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.

    About the Lecture

    The lecture Direct and Indirect Alloantigen Recognition by Peter Delves, PhD is from the course Transplantation Immunology. It contains the following chapters:

    • Direct and Indirect Alloantigen Recognition
    • Activation of Alloreactive T-Cells
    • The Immune Response to a Liver Graft

    Included Quiz Questions

    1. IL-2
    2. IL-4
    3. IL-10
    4. IL-12
    5. IL-13
    1. Allogeneic antigen presenting cells that express allogeneic MHC.
    2. Autoreactive T-cells.
    3. Memory T cells specific for allograft.
    4. Allogeneic antigen presenting cells that express self MHC.
    5. Self antigen presenting cells that express allogeneic MHC.
    1. T cells become activated followed by production of CD4 and CD8 effector T cells targeting the alloantigen.
    2. Allogeneic effector T cells secrete cytokines which induce graft rejection.
    3. CD4 effector T cells become activated and travel to allograft- CD8 cells are not involved.
    4. Allogeneic APCs will activate self CD4 effector T cells, mediating graft rejection.
    5. Cytokines produced by allogeneic CD4 cells will prevent invasion of CD4 and CD8 effector T cells from host.
    1. Treg cells
    2. Complement activation
    3. IL-2
    4. IFNγ
    5. IL-1

    Author of lecture Direct and Indirect Alloantigen Recognition

     Peter Delves, PhD

    Peter Delves, PhD

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