Mechanisms of host infection control in immunosuppressed and infection-prone individuals
Organ transplant patients usually have to take immunosuppressive drugs for the rest of their lives to prevent their bodies from rejecting the organs. This therapy suppresses the physiological immune response to tumors and infections. The therapeutic goal for this patient group is to achieve an optimal balance between immunocompetence and protection of the transplanted organ. The tendency to develop infections varies greatly from person to person. The researchers' goal is therefore to identify biomarkers that can reliably predict the individual risk of infection with opportunistic pathogens and the reoccurrence of chronic viral infections. This would enable timely therapeutic intervention and, if necessary, causal prophylactic intervention.
Immunosuppressive drugs used to prevent the rejection of a transplanted organ must be dosed very precisely. An overdose can be associated with significant side effects that are not limited to the host's limited immunocompetence. Therefore, so-called pharmacokinetic monitoring is carried out to determine the drug level in the blood in order to avoid toxic side effects. Since the immunocompetence of a human being is regulated in an extremely complex way, a dosage of immunosuppressants alone, according to a uniform (non-toxic) drug level, leads to different impairments of the immune system in different individuals. It is therefore necessary to investigate which deviations in which components of the immune system are responsible for a pathological susceptibility to infection in transplanted patients. To this end, functional immunophenotyping is performed in a prospective clinical study before and at various times after kidney transplantation. More than 200 different populations of immune cells in the blood and blood vessels will be quantified and their reaction to synthetic bacterial or viral components will be examined ex vivo. The scientists will compare these data with clinically relevant infectious events and evaluate them using bioinformatics.
Physiologically, the immune response to a transplant antigen that is foreign to the body is similar to that to a viral infection. Therefore, successful suppression of the rejection reaction also means that viral infections are more difficult to suppress. Some viruses that chronically infect a large number of people but do not cause clinical symptoms can be reactivated after transplantation. This can lead to pronounced damage to the transplant, e.g. with the cytomegalovirus (CMV) or the human polyoma virus 1, while others can lead to tumor diseases (herpes viruses, Epstein-Barr virus). In this project, CMV infection and reactivation are given special priority, since this virus is very common in donors without symptoms and is transmitted to the transplant recipient despite antiviral prophylaxis. With comparable immunosuppressive therapy, these events occur with an incidence of about 50%. This raises a number of clinically relevant questions:
- Can parameters be identified that protect against clinically apparent CMV infection in a high-risk group (CMV-negative recipient receiving an organ from a CMV-positive donor)?
- Is there a correlation between the type and intensity of immunosuppression and CMV infection/reactivation?
- Are there ways to maintain/generate anti-CMV protection without compromising the graft?
- Can anti-CMV prophylaxis be avoided with the appropriate biomarker constellation, thereby reducing the associated side effects?
