Organ transplantation: Disarming instead of suppressing

6. October 2014

In the world of organ donation, the option of disregarding tissue compatibility and being able to discontinue immunosuppressant use has thus far been more desire than reality. With new strategies in tolerance induction, the era of lengthy searches for a suitable donor could be coming to an end.

There are powerful agents which enable the transplanting of a kidney, a heart or a liver from one human permanently to another, thus saving the life of the recipient. Drugs such as cyclosporine suppress the immune system and prevent it from carrying out its duty and destroying or expelling everything alien to the body. For some time now we have wanted to do without the active ingredients whenever possible, in whole or in part. Could the immune system somehow be persuaded that a foreign organ can be regarded as a friend and not as an unwanted intruder? Even though recent clinical studies are only based on small numbers of patients, it seems as if the body could be educated for tolerance to foreign entities.

Chimerism instead of immunosuppression

For about 60 years immunologists have repeatedly learned by experience that in mice and rats such tolerance can be achieved more easily than in larger animals such as monkeys or in particular humans. Newborn rodents do not have a mature immune system and they therefore accept skin or an organ transplant much more readily. With regard to humans the magic word here is “chimerism”, a phenomenon which eventually should even enable organ transplants when the MHC alleles of donor and recipient differ significantly. In order to generate such a “mixed immune system”, the recipient receives not only the organ needed, but also bone marrow with haematopoietic stem cells from the donor.

In the mid-nineties the first kidney transplants preceded successfully using allogeneic bone marrow transplantation. In many cases, the kidneys functioned flawlessly without signs of rejection despite the patient having discontinued use of immunosuppressants. The inactivation of one’s immune system as a prerequisite for bone marrow transplantation is admittedly associated with severe toxic reactions – an argument that speaks against the routine use of this technique.

Allogeneic transplantation of stem cells and kidney

Combined kidney and bone marrow transplants between siblings were carried out in 1998 by Thomas Spitzer from Massachusetts General Hospital in Boston. One patient, whose kidneys failed due to a multiple myeloma, lived in 2011 still healthily with the transplanted organ and without new onset of the tumour. In 2002 doctors from Boston went a step further: they transplanted five kidneys in HLA-divergent donor-recipient combinations. In four cases, the transplant was successful and the new kidney was not rejected – without immunosuppression. For at least one patient this situation has now remained so for more than ten years.

Non-myeloablative conditioning

About 30 years ago the transplantation of bone marrow and kidney or liver were events that took place independently of one another. The donated bone marrow helped in treating a haematological disorder. Only years later after the kidney failed would a second transplant take place – from the same donor. After “myeloablative conditioning” using strong irradiation and cyclophosphamide had provided a tolerance to the donor, the subsequent transplantation of the kidney produced normal functioning without complications – and without immunosuppression. More and more often however scientists and physicians have in recent times been successful with a “non-myeloablative treatment”. Significantly lower doses of radiation and a weaker inactivation of the original haematopoietic stem cells through cytostatics allow the initial bone marrow to survive and regrow. A few weeks after transplantation a chimeric blood production centre arises.

Quite often, this results in a graft-versus-host reaction (GvHR) which usually nevertheless is much weaker than shown in previous transplantation studies using complete T-cell depletion. The group in Boston inactivates T-cells here using an anti-CD2 antibody, cyclophosphamide and irradiation of the thymus. Rituximab against B-cells should ultimately prevent an antibody-mediated response against the new organ.

Differing “blood counts”

Two years ago, a group led by Suzanne Ildstad from the University of Louisville in Kentucky published a study of eight kidney recipients in Science Translational Medicine. All donor-recipient pairs differed significantly in their transplantation antigens. A whole-body irradiation using 200 Centigray in combination with fludarabine and cyclophosphamide ensured that a biotechnologically purified stem cell concentrate together with a mixed population of “graft facilitating cells” could settle in the recipient. Together with the stem cells, doctors also transplanted in each a donor kidney. A sustained chimerism yielded the outcome in five of the eight cases that the initial immunosuppression was able to be discontinued and the organ carry out its role permanently in the new body.

The strategies of the groups from Louisville and Boston resulted in the organ recipients having different “blood counts”: the treatment using only cytostatic and anti-CD2 (Boston) produced a transient chimerism in which the own immune system with time regains the upper hand. The risk thereby of a GvH reaction is significantly lower, nevertheless infections or inflammations of other types could lead to a rejection, even years after transplantation. A stable “complete” chimerism (Louisville) probably means less risk for the transplant, but more risk of GvH illness, which up until the present however has not been observed.

Which strategy is better is something currently being investigated by several research groups both in Europe and in the USA. It’s still the case that “preconditioning” of the bone marrow and subsequent stem cell transplantation is associated with considerable risks and increased mortality and taking this option in exchange for doing without immunosuppressants often cannot be justified. If it’s not a kidney, but a heart or liver being transplanted, the general condition of the patient argues against such stress.

HCV infection provides tolerance

A few weeks ago a research group in Munich, Hannover and Barcelona published results of liver transplantation in patients with latent Hepatitis C virus (HCV) infection. Despite an active immune system, about half of the patients are not dependent on the administration of immunosuppressants. Apparently, the researchers speculate, the viruses induce tolerance which not only protects them, but also protects the transplanted organ. Looking at the genes of these tolerant patients, Ulrike Protzer of the Technical University of Munich and her colleagues found brisk activity in the type I interferon system, responsible for regulation of antiviral responses. Protzer therefore speculates:“When the interferon system, as in some chronically infected patients, is constantly activated, other immune responses are down regulated in order to protect the body. This condition might work like a natural immunosuppressant effect and reduce the rejection of the organ”.

With Treg and MREG against rejection

An important role in suppressing alloreactive responses could be being played by regulatory T cells. In the ONE study, about 13 partners have joined together from across four European countries and the United States in order to investigate the effects of such regulatory cells as the TCell line (Treg), as well as of macrophages (MREG) and dendritic cells. Previous pilot experiments indicate that such regulatory cells – in particular MREG – can induce an immune tolerance for transplanted kidneys.

Organ transplants between strangers without immunosuppression

Far too little is known about markers and indicators which point to a tolerance or even to a dissatisfaction experienced by the body with regard to the new organ. As such the cessation of immunosuppressant use in the context of clinical trials as well is still a gamble. Even when many organs have meanwhile been functioning for ten or more years without problems, this is no guarantee against a possible rejection. Starting with the combined transplantation of bone marrow and kidney or liver, a gentler path to stable organ replacement without constant propitiating of the defence system could develop.

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