Tissue Typing, Immunosuppressive Drugs and GVHD

00:01 This need to match the MHC between the donor and the recipient necessitates tissue typing of the donor and the recipient. This patient has developed renal failure and needs a kidney transplant. He has been typed for HLA-A, HLA-B and HLA-DR.

00:25 And as we can see, this particular individual is HLA-A2, A5, B7, B13 and DR2, DR1.

00:34 Here we have a number of different patients that are awaiting a transplant.

00:41 They are placed on a register with many others.

00:44 Each of whom are likely to have different HLA types as shown on this slide.

00:51 When tissue typing occurs, a potential donor is HLA typed and each kidney is sent to a hospital where a good HLA match patient is waiting to have the graft transplanted.

01:08 A blood sample from the donor is also sent to the hospital.

01:13 In the cross match, donor B-cells are mixed with recipient’s serum.

01:18 In this case, preformed antibodies are binding the donor cells.

01:23 This transplant cannot take place.

01:27 However here we see that the recipient has no antibodies against donor cells and the transplant can go ahead.

01:36 Preformed anti-donor antibodies can result from pregnancy, blood transfusion, or indeed a previous transplant.

01:47 Let’s look at the mechanisms of action of immunosuppressive drugs.

01:51 These are almost always required, because it’s almost impossible to get an identical match between the donor and the recipient unless there is an identical twin.

02:01 There is almost always some mismatch as regards the MHC.

02:08 Here we can see an anti T-cell receptor antibody that is used to block the interaction between the T-cell receptor and the MHC.

02:19 The drugs, cyclosporine and FK506 inhibit the calcineurin signaling pathway.

02:30 CTLA4-Ig interferes with the co-stimulatory interaction between B7 and CD28, thereby preventing co-stimulation and activation of T-cells.

02:48 Both of these approaches, using cyclosporine, using FK506, using CTLA4-Ig, using anti T-cell receptors, at the end of the day they have the same effect.

03:00 They block the activation of T-cells and block the subsequent production of interleukin-2.

03:06 Antibodies against the interleukin-2 receptor can be used to prevent T-cell stimulation by this particular cytokine.

03:19 Therefore signaling through the IL-2 receptor leading to lymphocyte activation will be blocked.

03:27 The immunosuppressive drug rapamycin inhibits mTOR which is involved in the signaling process.

03:36 And therefore, there is prevention of proliferation of the lymphocytes.

03:41 And finally, azathioprine and mycophenolate can also interfere with the proliferative process and act as immunosuppressive drugs.

03:52 One normally thinks about the recipient rejecting the graft, but the opposite situation can occur when an individual is being given a hematopoietic stem cell transplantation.

04:04 This can result in graft versus host disease.

04:09 In this situation, you have an individual, perhaps a patient with leukemia that is being treated with radiation or with cytotoxic drugs that is damaging their own immune system.

04:22 They are then given a transplant of hematopoietic stem cells, perhaps from a bone marrow.

04:28 Could be from cord blood, could be from peripheral blood.

04:32 These cells are of course immune system cells that are being used for the transplantation.

04:40 And the donor T-cells can recognize the foreign MHC on the recipient cells, leading to the death of those cells and causing graft versus host disease.