3 research outputs found
Innate and acquired immunity to Leishmania in humans : the role of the host versus the parasite
Leishmania are intracellular protozoan parasites of macrophages which
induce chronic diseases in man. The study of this parasite has been
instrumental in elucidating many facets of the immune system. Our study
set out to understand the immune regulatory mechanisms involved in
resistance and susceptibility. We have used in vitro stimulation of
peripheral blood mononuclear cells and measured cell proliferation,
cytokine rnRNA or protein induction and analyzed phenotype of cells by
flow cytometry. Our results show that there are innate elements of immune
reactivity to Leishmania antigens in unexposed donors involving cellular
proliferation of NK cells and IFN[gamma] secretion. These responses are
neither induced by the abundant antigens on the surface of Leishmania
promastigotes nor mycobacterial antigens tested. Low molecular weight
fractions of Leishmania could induce proliferative and cytokine responses
in cells of both healthy and infected individuals. However, response to
the high molecular weight antigens was a feature of the healthy
individuals.
The relevance of an NK dominated response has been tested in a
Leishmaniasis endemic area where the role for NK cells in protection has
unfolded. Consistent with our previous findings, NK and CD8+ cells
proliferated in response to Leishmania antigen stimulation. Our results
also suggested the presence of a low background level of large NK cells
as an important aspect of the protective mechanisms that operate in the
Leishmaniasis-resistant endemic controls which is also established
following cure from the disease. Based on the results obtained we
concluded that NK cells are involved in protection from and healing of
Ethiopian cutaneous Leishmaniasis.
As part of the quest for identifying the stimulatory molecules of
Leishmania to which PBMC from non-exposed healthy individuals respond, we
have tested a Leishmania homologue of receptors for activated C kinase
(LACK) from L major as well as three amastigote antigens from L. pifanoi.
The immuno-dominant molecule LACK induced in vitro proliferation of NK
and CD8 cells coupled with high levels of IFN[gamma] and IL- 10
production. Of the amastigote antigens, P-2 and, to a lesser extent, P-8
induced proliferation in cells of healthy individuals. These responses
were reduced in the presence of anti-MHC class 11 antibodies.
We tested whether properties of the infecting parasite could influence
induced immune response. Our results showed that regardless of whether
cells were derived from healthy individuals, or from patients with
localized (LCL) or diffuse (DCL) cutaneous Leishmaniasis,
DCL-promastigotes preferentially induced mRNA for IL-10 while induction
of IFN[gamma] was a feature of LCL-promastigotes. The importance of the
properties of the infecting parasite is illustrated in a case report
where a slow growing form of Leishmania showed atypical clinical symptoms
in a Swedish man 15 years after infection. The focus of this thesis has
been the innate and acquired immune regulatory mechanisms involved in L
aethiopica infection in human. The possible cross species immune response
by proteins derived from other Leishmania species are investigated in an
attempt to evaluate the potential use of such proteins in a universal
vaccine