Chemistry Reference
In-Depth Information
2 IMMUNOSUPPRESSION INDUCED
BY METALS
A special effect of some metals is skewing of the T-
helper cell response toward type 1 or type 2. This was
fi rst observed for zinc as an adverse effect on Th2
cells (Prasad, 2000). A skewing favoring a Th2 type of
response has been observed during lead and mercury
exposure (Heo
et al.,
1997). The latter fi nding correlates
with a decreased resistance to intracellular pathogens
after exposure to mercury (Bagenstose
et al.,
2001; Sil-
bergeld
et al.,
2000) and lead (Dyatlov and Lawrence,
2002), which concurs with the observation that a Th1
response is needed to effi ciently handle intracellular
pathogens (Igietseme
et al.,
2004).
2.1 General Considerations
Immunosuppression is a reduction in the normal
immune function, irrespective of the magnitude. This is
uncomplicated for xenobiotics such as cytotoxic drugs
that cause a severe reduction in immune functions.
However, many metals (and other xenobiotics) cause
only a mild-to-moderate reduction of the immune func-
tion, and the direct consequences for the host are usu-
ally marginal and self-limited.
Immunodepression
has
been proposed as a term for such mild-to-moderate sup-
pression of the immune function (Descotes, 1999). This
concept is potentially very useful for metals but would
necessitate an agreement on how to defi ne immuno-
depression and immunosuppression, including dose
considerations. Because such an agreement is lacking,
the term immunodepression will not be used in the
following text, although the concept is acknowledged.
2.4 Experimental Host-Resistance
Challenge Systems
The perceived genuine functions of the immune
system are to protect the host from pathogenic agents
such as microorganism (including bacteria, viruses,
parasites, and fungi); to suppress development of
neoplastic cells and eliminate such cells; and fi nally
to eliminate or at least contain other non-self compo-
nents, for example, crystalline material like silica. The
mere observation of a signifi cant effect of a metal on
a certain immune parameter
in vivo
should, however,
not be interpreted as a signifi cant immunosuppression.
The reason is the redundancy and the reserve capacity
of the immune system (Section 1.3). Redundancy is the
multiplication of crucial mechanisms in the immune
system: if a specifi c function is affected, other mecha-
nisms may carry out the jeopardized function. Reserve
capacity means that the integrated immune system is
capable of carrying out its genuine functions although
certain immune parameters are suppressed.
To better assess the functional importance of the
immunosuppressive effects observed for several met-
als
in vitro
and in
vivo
, a number of experimental
infectivity and neoplastic models—host resistance
challenge models—have been developed. Perhaps the
best-examined metals in this respect is lead, which
causes enhanced susceptibility whether the challenge
is with virus (Gainer, 1974; Gupta
et al.,
2002; Youssef
et al.,
1996), bacteria (Cook
et al.,
1975; Dyatlov and
Lawrence, 2002; Hemphill
et al.,
1971), or tumors
(Kerkvliet and Baecher-Steppan, 1982; Kobayashi and
Okamoto, 1974). Another example is mercury, which
causes reduced resistance to viruses (Ilback
et al.,
1996),
bacteria (Koller, 1975), and parasites (Bagenstose
et al.,
2001; Silbergeld
et al.,
2000).
2.2
In Vitro
Studies
A large number of
in vitro
studies have demonstrated
that metals may suppress the function of all immune
cells (Lawrence, 1981), including T (Colombo
et al.,
2004; Mattingly
et al.,
2001; Shen
et al.,
2001; Shenker
et al.,
1992) and B (Gallagher
et al.,
1995; Shenker
et al.,
1993) cells, as well as monocytes/macrophages (Sakurai
et al.,
2004; Wataha
et al.,
2000).
In vitro
observations
are critically dependent on the metal concentration, the
cell type(s), the duration, and exact conditions of the
culture, including the oxygen pressure and the oxida-
tive status, as well as the strain and species from which
the cells are derived. As a consequence, contradictory
results have often been reported, and
in vitro
studies
should be treated cautiously and as an indication of
possible
in vivo
effects only.
2.3
In Vivo
Studies
In vivo
studies using animal models have estab-
lished the ability of metals to act as immunosuppres-
sants on various functions on the immune system in
the intact organism. This is especially true for organ-
otins (Battafarano
et al.,
1998; Smialowicz
et al.,
1990;
Vos
et al.,
1984), arsenic (Burns
et al.,
1991), cadmium
(Borgman
et al.,
1986; Fujimaki
et al.,
1983; Koller
et al.,
1975; Krzystyniak
et al.,
1987), lead (Lawrence, 1981;
McCabe
et al.,
1999), inorganic as well as organic mer-
cury (Abedi-Valugerdi
et al
., 1997; Christensen
et al.,
1996; Ellermann-Eriksen
et al.,
1994), and nickel (Dogra
et al.,
1999; Harkin
et al.,
2003; Smialowicz
et al.,
1987).
2.5 Clinical Immunosuppressive Effects
Despite the evidence that certain metals have a
significant effect on the ability of the immune system
