well-tolerated
protocol,
however,
our
research might be of interest to all patients needing solid organ transplantation.” In the 50 years in which solid organ transplants have
Mixed chimerism been used, major
improvements have been made in ensuring success for the initial year following the procedure. For example, approximately 95% of kidney transplants will survive the first year. However, after this first year a constant number of organs is lost every year. This is due to two important factors: chronic forms of rejection by the body, and the toxicity of the immunosuppressive drugs used to protect the organs from this rejection. For this reason, the Nephrology Research Laboratory of Zurich have been looking into ways of establishing a state of immunological tolerance in which the immune system of the recipient is manipulated in a way that it will accept a foreign organ as though it is self-tissue. “The only way in which this has been
achieved successfully so far in kidney transplantion is by combining the kidney transplant with a bone marrow transplant from the same donor,” says Fehr. “The engraftment of bone marrow cells from the donor establishes a state called mixed chimerism, in which the recipient’s immune system is made up of a mixture of cells from their own immune system and the donor’s. The cells of each person’s immune system that are predisposed to attack foreign cells will be cancelled out from the repertoire as
“The only way in which this has been achieved successfully so far in kidney transplantion is by combining the kidney transplant with a bone marrow transplant from the same donor”
they mature in the thymus. What is left is a mixture of mature donor and recipient immune cells that are not programmed to react to each other - or the newly transplanted kidney.” The difficulty lies in establishing this
state of mixed chimerism. To do a bone marrow transplant, conditioning therapy is needed, and at present the protocol for this therapy is very aggressive, involving
www.projectsmagazine.eu.com
chemotherapy and sometimes total body irradiation or total lymphoid irradiation. “Unfortunately, this therapy is so harsh that not everyone who needs a kidney transplant can actually tolerate it,” says Fehr. “The proof of principle that you can induce tolerance with bone marrow transplants is there, but we do not have protocols that are widely useable yet because of the levels of toxicity involved.” Cippà, who has led much of the research
into developing new protocols through his PhD, explains some of the breakthroughs that he has made. “One of the most important new factors that we have introduced to these protocols is a new class of drug that modulates apoptosis of lymphocytes,” Cippà explains. “Our idea was to use Bcl-2 inhibitors in order to find a new way to induce mixed chimerism. These drugs can be used to modulate the mechanism of apoptosis – programmed cell death – in lymphocytes, which are the primary barrier to foreign tissues
successfully remaining within the body. We hoped that by using these drugs, which have previously been used in patients with lymphomas, we might reduce the need to administer chemotherapy or irradiation.” Initially, tests were carried out to see these drugs had a beneficial
whether
effect in general on transplantation, and the results were resoundingly positive, showing that Bcl-2 inhibitors could indeed inhibit graft rejection. The second step was to integrate the drug into the tolerance protocol. “We found that by using a combination of the Bcl-2 inhibitor ABT737 with cyclosporin A - a commonly used immunosuppressive drug - for 2 weeks, we were able to induce mixed chimerism with a modest dose of bone marrow cells and without irradiation or chemotherapy. This was one of the most important findings we obtained during the project.” Another part of Cippà’s project was focused on the role of memory T cells. “At
66
Apoptosis modulation
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116 |
Page 117 |
Page 118 |
Page 119 |
Page 120 |
Page 121 |
Page 122 |
Page 123 |
Page 124 |
Page 125 |
Page 126 |
Page 127 |
Page 128 |
Page 129 |
Page 130 |
Page 131 |
Page 132