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Project

Polyclonal B-cell activation in human African tryponosomiasis (HAT): impact on acquired immunity and on rapid diagnostic tests. (HAT-PolyB VL)



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.




Date:1 Sep 2009  →  31 Dec 2012