Beschrijving

Mouse-models help to understand host-pathogen immune interactions and serve as model for vaccine development in human African trypanosomiasis (HAT) but their validity for what happens in man remains largely unknown. A better understanding of the immune deregulation observed in HAT, especially related to the B-cell compartment, is therefore needed and may have implications on clinical management and control of other infections as well.

While HAT is clearly associated with a polyclonal B-cell activation, little is known about the fate of this B-cell population upon activation. Trypanosoma brucei infection in mice results in loss of splenic marginal zone B-cells and loss of the vaccine-induced protective immunity against other infections. This was observed in a DTPa (diphtheria, tetanus and B. pertussis) vaccination model (Radwanska et al. 2008) confirming earlier findings in a T. spiralis immunization model (Onah& Wakelin 2000). Recent results indicate that the mechanisms at work are not associated to infection-associated immunosuppression. Indeed, even after cure of trypanosomiasis, vaccine induced memory in case of the DTPa model did not return. These results indicate that T. brucei infections can give rise to general B cell memory destruction, and we hypothesise that there might be a similar clinical impact in humans, but this remains to be demonstrated. Secondly, the uncontrolled production of antibodies after polyclonal B-cell activation in HAT patients is known to induce cross-reactions (and thus false positive tests) in a number of diagnostic tests for infectious diseases. While a well known phenomenon in laboratory studies, again, its clinical importance has hardly been studied. The situation is particularly worrying in the current context of HAT control in central-Africa, where WHO and other control agencies push for more integrated case management of HAT. This means that HAT patients are now taken care of in primary care centres and hospitals, whereas in the past they would have been cared for in dedicated “vertical” structures. The integrated approach poses several challenges for clinical case management, mainly in terms of individual and programmatic management of major co-infections, such as HIV or malaria. For HIV as well as for malaria, rapid diagnostic tests (RDT) are increasingly being applied at primary health care level - and in the case of malaria even at community level. We fear that in HAT patients, the above mentioned issue of cross-reactivity, if not correctly addressed, may lead to clinical case management problems, if the issue is not addressed. Indeed, our preliminary data showed that up to 60% of non-HIV infected HAT patients in Mbuji Mayi showed positive results in commonly used HIV RDTs. Therefore, the following research questions arise:


- Does HAT eliminate memory B-cells and acquired immunity against other pathogens, and is this effect reversible upon cure from HAT?

- Are memory T-cells affected?

- Can vaccine-induced protection be restored by vaccination after treatment of HAT, f necessary?

- What is the impact of HAT on the performance of RDTs for other infections, including HIV and malaria, and how can we improve diagnostic strategies?


To address these questions, we will identify and follow-up a group of HAT infected patients and non-HAT infected controls. We will assess the following parameters:

- Numbers of circulating memory B- and T-cells

- Vaccine induced humoral immunity, before and after treatment of HAT and upon subsequent vaccination

- T cell independent B cell activity

- Cell mediated immunity

- Accuracy of RDTs for HIV and malaria

Besides direct implications for HAT clinical management, the obtained results will improve our understanding of how deregulation of the B-cell compartment can affect immunity towards unrelated infections. This could provide important insights in vaccine failure in particular in tropical regions where co-infections are frequent. Results will also lead to recommendations for improved diagnostic and immunization policies in HAT endemic regions. In conclusion, the project will generate knowledge and have impact on control of infectious diseases, not only in HAT but also in other infections.


AcroniemHAT-PolyB VL
StatusVoltooid
Effectieve start/einddatum1/09/0931/12/12

ID: 1087978