Study gives hope for life without immunosuppressants after organ transplantation

An international team led by Hannover Medical School has succeeded in significantly improving long-term survival after transplantation in Göttingen minipigs by genetically modifying the donor lungs – without the otherwise necessary lifelong suppression of the immune system (immunosuppression therapy). In 2026, the first people are to receive a genetically modified lung, as the Director of the Institute for Transfusion Medicine and Transplant Engineering at the Medical School and co-founder of Allogenetics, Prof. Rainer Blasczyk, told heise online.

Although the results of organ transplantation have steadily improved, the lifespan of the transplants does not match the life expectancy of the patients. Especially in lung transplants, the long-term survival rate of transplants is low. During an organ transplant, the recipient's immune system recognizes certain molecules on the surface of the donor organ as foreign. These molecules are called MHC (in humans HLA, in pigs SLA – see box). They are also known as tissue markers and function like an identifier that the immune system uses to distinguish between "autologous" and "foreign".

Major Histocompatibility Complex​ (MHC)

MHC molecules (Major Histocompatibility Complex) are proteins on the surface of almost all body cells that play an important role in immune recognition. Their main function is to present peptides (short protein fragments) to the immune cells so that they can distinguish between "self" and "foreign".

There are two main classes of MHC molecules:

1. MHC class I molecules are found on almost all nucleated cells. They present peptides from the cell interior, which can originate from viruses or tumors, for example. If a CD8 T cell recognizes a foreign peptide on an MHC I molecule, this leads to the destruction of the infected or malignant cell.

2) MHC class II molecules are mainly found on specialized immune cells such as dendritic cells (for antigen recognition), macrophages and B cells. They present the T cells with peptides that have been taken up from outside the cell, for example from bacteria.

The genes that code for the MHC molecules are among the most variable in the entire genome. In humans they are called HLA (Human Leukocyte Antigen), in mice H-2 and in pigs SLA (Swine Leukocyte Antigen).

This high variability of the MHC molecules is important on the one hand in order to be able to recognize as many different pathogens as possible. On the other hand, it poses a major challenge in transplantations, as differences in the MHC molecules between donor and recipient are recognized by the immune system as "foreign" and can trigger a rejection reaction.

If the MHC molecules of the donor and recipient are very different, the immune system triggers a reaction to destroy the foreign organ – also known as rejection. To prevent this, patients must take medication after a transplant to suppress the immune system. Although this does not completely prevent rejection, it can significantly delay it.

However, these drugs are often associated with serious side effects and are a lifelong burden for patients. "As the problem of rejection has been unsolved for decades, we have been looking for a completely new way to solve the problem: instead of blinding the recipient's immune system with immunosuppressants, we want to make the organ immunologically invisible," explains Prof. Blasczyk.

It would therefore be a major step forward if the donor organs could be modified in such a way that they are no longer recognized as foreign by the recipient's immune system. Then the immune system would not have to be suppressed to prevent rejection. Transplant survival could be significantly increased and patients would be spared the side effects of immunosuppressants after transplantation.

A promising approach for this is to specifically reduce the production of these "foreign" MHC molecules on the donor organ. This is precisely what the researchers tested in this study on lungs from Göttingen minipigs.

The aim of the study was therefore to investigate whether targeted downregulation of SLA expression by genetically modifying the lungs can improve their survival in a pig transplant model and prevent rejection even without immunosuppression. The aim is to reduce transplant rejection and the burden of immunosuppression for patients.

Preparation of the donor lungs

In lung transplantation between genetically different minipigs (allogeneic lung transplantation), scientists have tested a new method to improve the survival time of the transplants.

After removal, the donor lungs were placed in a special organ preservation system that supplies the lungs with nutrients and oxygen outside the body. This is known as ex vivo lung perfusion (EVLP for short). In this system, the lungs were then treated with viral vectors and thus genetically modified.

First, a substance called protamine sulphate was added to the fluid flowing through the lungs. This substance supports the uptake of the viral vectors by the organ cells. Then a large quantity of specially developed viruses, so-called "lentiviral vectors", were introduced into the system. These viral vectors circulated in the lungs for about two to three hours. During lung perfusion, the vectors deliver the necessary genetic information that causes a stable downregulation of the MHC molecules in all cells of the organ. "We initially assumed that the viral vectors only genetically modify the inner walls of the blood vessels – the so-called endothelial cells as the interface between donor and recipient–, but then we were pleased to see that all cell types of the lung are reached," explains Prof. Figueiredo.

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The lungs were kept at body temperature in order to create optimal conditions for the uptake of the viral vectors into the lung cells. After this treatment, the fluid in the system was replaced by a mixture of pig blood and a special nutrient solution.

In the treatment group, the viral vectors contained genetic instructions to reduce the tissue characteristics of the lung (SLA class I and II). In the control group, however, the viruses did not contain such specific instructions. This procedure enabled the researchers to genetically modify the entire lung prior to transplantation. The aim was to modify the lung so that it would be less recognized as "foreign" by the recipient's immune system, thus increasing the chance of a successful transplant without permanent immunosuppression.

Results give hope

While all untreated lungs were rejected within a maximum of 98 days, five out of seven animals (71.4 percent) with the genetically modified lungs survived for more than 2 years – without any immunosuppression, which was discontinued after 28 days.

The recipients of these SLA-suppressed lungs also showed significantly lower levels of donor-specific antibodies and inflammation-promoting messenger substances (cytokines) in the blood compared to the control animals. The proliferation of immune cells that specifically attack the foreign organ (alloreactive T cells) was also reduced.

The fact that the genetic modification did not lead to an excessive activation of certain immune cells (natural killer cells) that specialize in cells lacking MHC is due to the fact that a residual amount of SLA molecules was deliberately left on the lung.

The study shows that the genetic modification for the targeted reduction of tissue characteristics on the donor organ – can improve the survival of the transplant and prevent rejection even without the stressful immunosuppression –. The research team hopes that this promising approach can also be transferred to humans in the future in order to significantly improve the quality of life and prognosis of lung transplant patients. It is remarkable that the animals that are still alive are now older than six years.

Blasczyk and his team would have had no qualms about testing the modified organs directly on humans. The company, which was founded in 2022, would like to be much further along, but the approval process for animal testing at the Ministry of Agriculture takes around a year. Blasczyk believes this could be faster. However, as soon as the clinical trial in humans starts, it is not initially planned to discontinue the immunosuppressants as quickly as in pigs, but rather in small steps.

Pigs looking for a home

Several Göttingen mini pigs weighing around 60 kilograms are currently looking for a home. Anyone who can imagine taking some in is welcome to contact the editorial team.

(mack)