IMMUNOLOGY TOD.AY

ost parasites pass through

complicated life cycles

with different stages,

frequently colonizing

various tissues of the host, and conse-

quently ccz+sin a great variety of antigens.

Over millions of years, parasites have de-

veloped sophisticated strategies to adapt to

their hosts and to evade attacks by the im-

mune system. As a result, parasite infec-

tions tend to be chronic and the quality of

the immunological responses varies consid-

erably in the different phases of infection.

The studies of the host-defense mechanisms

against parasites are aimed at the develop-

ment of prophylactic and curative means

but, at the same time, they provide important

insights into general principles of the regu-

lation of immunity.

Cells and cytokines involved in

protection and immunopathology

Infections with parasites are often charac-

terized by polarized T-cell responses that

control the development of either immunity

or pathology. Cytokines Froduced by the

T helper 2 (Th2) subset ol CD4+ cells are

thought to be involved in granuloma for-

mation and pathagenesis resulting from

infection with the helminth Skistosorrzn

mnsoni. However, hepatic granuloma for-

mation in mice in which the interleukin 4

(IL-41 gene has been knocked out (IL-4-/-I

was found to be similar to that in infected

wild-type mice (E. Pearce, Ithaca, NY). Tumor

necrosis factor IY (TNF-a) contributes to dis-

ease and death in IL-K- mice. These data

show that IL-4-independent pathways are

involved in the generation of Th2-like re-

sponses during acute disease. In the chronic

phase of S. rrmrtsarri infection, the down-

modulation of granulomatous inf!am-

mation may be a result of the regulation of

Th2 responses by CDS’ T cells. Pearce

reported on his studies to elucidate the

cytokine cascade involved in granuloma

modulation and demonstrated that IL-4

promotes interferon y (IFN-y) production

by type 1 CDS’ T cells.

The differentiation of uncommitted T cells

towards a Thl phenotype is driven by IL-12.

In a wide range of models of infectious dis-

ease, IL-12 has been shown to confer pro-

tection when administered at the time of

infection. The combination of IL-12 and

Pe:ltostam (sodium siboqluconate), an

antimony-based drug commonly used for

the treatment of human leishmaniasis, in-

duces healing in Lrishmn~rin rr@tr--infected

mice even during progressive disease

13’. Scott, Philadelphia, PA). This finding

shows that IL-12 can switch an established

Th2 response to a protective Thl pattern

when the parasite ‘burden is reduced. It

should be noted, however, that the switch

occurs at the level of the T-cell population

and is probably based on a fraction of naive

cells or Thl cells rather than a change of

clonal phenotype.

Early after infection, L. mnjtlr stimulates

IL-12 production in genetically resistant and

in susceptible mice. By contrast, a strong

upregulation of IL-12-receptor expression is

only detected in resistant and not in suscep-

tible mice (Scott). The resulting limitation of

IL-12 responsiveness, which presumably

contributes to the lack of ThI development

in susceptible mice, can be overcome by ad-

ministration of exogenous IL-12, which in-

duces the upregulation of IL-12-receptor

expression.

An additional group of cytokines - the

chemokincs - has recently been shown to be

involved in microbial infections. Most of the

01 chemokines attr I- neutrophils, whereas

/3 chemokines ;_t o monocytes, lympho-

cyte subpopulations ,,nd naturai killer cells.

It was observed that in patients with Iocal-

ized cutaneous leishmaniasis, skin lesions

are characterized by high lewls of mono-

cyte chemoattractant protein 1 (MCP-1). By

contrast, expression of macrophage inflam-

matory protein la (MlP-la) predominates

in the non-healing lesions of diffuse cuta-

neous Ieishmaniasis (H. Moll, Wiirzburg).

This suggests that, in addition to the lym-

phokinc profile, the pattern of chemokine

expression correlates with the type of dis-

ease, extending the scope of candidates for

cytokine-based interventions.

Effector mechanisms

Cytokines such as IFN-y and TNF-ru. are

critical for the induction of effector mecha-

nisms that mediate the antimicrobial defense.

The bulk of evidence indicates that this ac-

tivity can be assigned to nitric oxide (NO) or

its reaction products. Notably, recent evi-

dence strongly suggests that NO-dependent

killing of infectious agents is also used by

human macrophages. NO is not only in-

volved in the elimination of microbes for

overcoming acute infections, but also re-

stricts the growth of organisms that per&l

in latently infected hosts. C. Bogdan

(Eriangcn) reported that FerGtpnce of L.

r~mjor in clinically cured mice is accompanied

by the sustained expression of cytokine-

inducible NO synthase CiNOS), and inhibition

of iNOS activity results in reactiv&iion <if CU-

taneous leishmaniasis. The majority of per-

sisting L&lJnln/?in is associated With iNOS

cells, some of which are possibly fibroblasts.

Studies in elihn showed that fibroblasts can

take up L. ~nnjor, but fail to kill the parasites.

IMMUNOLOGY TODAY

Genetic regulation of the host response to infections Natural resistance or susceptibility to infec-

tions with intracellular pathogens tmyco-

bacteria, Snlrrturzclln t!jpIz~i,nzrrizzrzz and L.

slozzowai) is determined by the gene Be‘s/

It!///_s/z, now designated Nmrrr/rl (natural-

resistance-associated macrophage protein 1).

This has been confirmed recently by experi-

ments with transgenic mice showing that a

Nrnzzrjrl construct derived from a resistant

strain confers the resistance phenotype to

an otherwise susceptible genetic back-

ground (E. Skamene, Montreal). Members

of the Nrnzrr/~ gene family have been iden-

tified in most species, uncovering an ancient

group of related Nramp proteins that are

presumed to be involved in membrane

transport or signal transduction. It has been

postulated that the Nrampl protein is local-

ized in the phagosome membrane of

macrophages, where it may transport a

charged substrate, possibly nitrate or nitrite,

to create an antimicrobial milieu.

The linkage between human NRAMPI

and susceptibi!ity to mycobacterial disease

is currently being analyzed. There is some

evidence for an association of NRAMPZ and

tuberculosis in epidemic outbreaks of the

disease, whereas no significant link was

found in endemic areas (Skamcnc). This

may reflect an involvement of NRAMPI in

early, natural susceptibility to tuberculosis.

Vaccination strategies For the development of an effective vaccine

against an infectious agent, it is necessary to

chara, :erize the type of immune response(s)

mediating protection, to identify the rel-

evant microbial antigens and to establish an

appropriate mode of delivery. All these

aspects were addressed at the meeting.

M.M. Simon (Freiburg) described the

mechanisms of immunity to Lyme disease,

which is caused by infection with the spiro-

chete B~rlrlin bzzr~&r~ri. The humoral im-

munity is essential for clearance of the bac-

teria, but T cells are critically involved in the

generation of an optimal antibody response.

B. bzrr@r@i may evade complete elimi-

nation by modulating its ?oat of outer

surface proteins (0s~) and binding host-

derived plasmin. This causes persistence

even in the presence of an ongoing immune

response.

invasion and tissue destruction by the

enteric parasite Ezztnt1zoeI7~ histd~tim is the

result of parasite adherence to and subse-

quent killing of host cells. Adherence is me-

diated by a surface lectin of the amoeba.

Vaccination trials in gerbils have shown that

a 125 amino acid fragment of the 170 kDa

subunit of this lectin confers protection

against amoebic liver abscesses (E. Tannich,

Hamburg). It is intriguing that this frag-

ment was recognized by about 80% of sera

from hsymptomatic E. Izi.~fol_~/ticn carriers but

only by 15% of sera from patients with

amoebic liver abscesses.

Over recent years, the development of

novel delivery systems has led to advanced

strategies for vaccination. These include

using IL-12 as an ndjuvant (Scott) and im-

munization with DNA such as a plasmid

encoding OspA of 6. btzr~~dorfcri (Simon). In

addition, specialized antigen-presenting

cells may be used for the generation of

immunity against parasite infections.

Dendritic cells are attractive candidates be-

.cause they have the unique capacity tcr in-

duce primary immune responses and retain

antigen in an immunogenic form for pro-

longed periods. The biological relevance of

this was shown in experimental cutaneous

leishmaniasis: treatment of mice with

dendritic cells that had been pulsed with

L. znzjclr antigen irz zlit~o induced resistance

against a subsequent challenge with virulent

parasites (Mall).

Future prospects Significant achievements have been made

with respect to the identification and mol-

ecular characterization of protective para-

site antigens and the dissection of immune

responses that mediate resistance or pathol-

ogy. However, parasite immunologists and

molecular biologists continue to face great

challenges. Many details of the mechanisms

that underlie antigenic variations remain

to be clarified, and the paradigm of lym-

phocyte subsets mediating detachable func-

tions with beneficial or detrimental effects

still needs critical evaluation. In the future,

the field of parasite immunology is ex-

pected to contribute further to our general

understanding of immunologically driven

disorders, since the features of parasite

infections closely resemble the general av-

enue taken by other, non-infectious chronic

diseases

Trends

The Trends section of Immunology Today covers up-to-date

developments and reports on recent immunologically relevant

meetings. If you would like your meeting to be reported by

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D,ECEMBER 1996