14 November 2022

Transplantation without immunosuppression

In a study conducted by Stanford Medical University on mouse models of diabetes mellitus, a new method of transplantation of islet beta cells of the pancreas secreting insulin has been tested. The method does not require subsequent immunosuppressive therapy, since the cells are treated in a special way before transplantation, which excludes rejection.

Transplantation of insulin-secreting beta cells of the pancreas requires chronic suppression of immunity to prevent rejection. In addition, there are methods of preparing the recipient's immune system for transplantation, but they usually include high-dose radiation and chemotherapy, which are too toxic for most people with diabetes.

Double transplantation

The essence of the approach is to perform two transplants instead of one. A few years ago, researchers from Stanford Medical University showed that replacing the recipient's immune system with the organ donor's immune system through blood stem cell transplantation before organ transplantation ensures that the organ will not be rejected by the body.

But to do this, you first need to destroy the recipient's own stem cells with high-dose radiation and chemotherapy, which are accompanied by severe, potentially fatal consequences and often lead to infertility. In addition, the "new" immune system attacks healthy tissues and organs that it perceives as foreign – a condition known as graft versus host disease.

Further studies have shown that before the donor's stem cells are injected, the recipient's immune system can be weakened, not destroyed. The result is a hybrid, or chimeric, immune system consisting of both donor and recipient stem cells, and the likelihood of a "graft versus host" reaction is reduced. The chimeric immune system is also less likely to reject a transplanted organ, especially if it is immunologically well matched. In 2020, the authors of the concept showed that most people who underwent kidney transplantation from siblings were able to refrain from taking immunosuppressive drugs for at least two years.

The conditioning regime for achieving chimeric immunity is too rigid for use in non-life-threatening situations, and organs must be at least partially immunologically selected to avoid rejection.

Three-stage preparation

In this study, Son Kim and colleagues experimented with a three-step approach to preparing recipients with diabetes for stem cell transplantation. They combined low doses of radiation, a single injection of c-Kit antibodies that selectively infect and destroy blood stem cells that give rise to immune cells, and a single injection of antibodies targeting mature T cells. The researchers showed that these three manipulations were enough to allow the donor stem cells to gain a foothold in the bone marrow of mice and create a fully functioning chimeric immune system without the serious side effects observed with other methods. Now these animals with diabetes were able to accept transplanted islet cells from a stem cell donor, even if the animal does not completely match the recipient immunologically.

The radiation dose in preparation for stem cell transplantation was reduced by 80%, and broad–acting chemotherapeutic drugs were replaced with targeted antibodies. The animals quickly regained the weight they had lost due to the disease and were able to maintain normal blood glucose levels until the end of the study - more than 100 days.

After three-stage preparation and two transplantations, the mice were no more susceptible to infection than the mice of the control group, which indicated the normal functioning of the chimeric immune system. The mice also retained fertility and produced healthy offspring

One of the limitations of the development is that both stem and islet cells must be taken from the same animal, and human islet cells are difficult to obtain. Kim and colleagues from Stanford University are currently investigating the possibility of growing and multiplying functional islets in vitro from pluripotent stem cells to obtain much more suitable material for transplantation.

Article by C.A.Chang et al. Curative islet and hematopoietic cell transplantation in diabetic mice without toxic bone marrow conditioning is published in the journal Cell Reports.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on Stanford Medicine: 'Gentle' islet cell transplant cures mice of diabetes with few side effects, Stanford Medicine researchers say.

Found a typo? Select it and press ctrl + enter Print version