Page 407 - Clinical Immunology_ Principles and Practice ( PDFDrive )

388 PARt tHREE Host Defenses to Infectious Agents

lipids presented by CD1c, and secrete many cytokines otherwise Our deepening understanding of the molecular events governing
associated with T cells, DCs, and macrophages. B-cell signaling via intracellular bacterial infections is allowing development of novel
MyD88 during S. typhimurium infection has been associated with therapeutic and preventive approaches. The need for such
B-cell production of IL-10, and mice with B-cell-specific deficiency interventions is becoming all the more pronounced in the face
in MyD88 were more resistant to infection demonstrating that, of increasing levels of antibiotic resistance of bacteria, such as
like T cells, B cells can perform regulatory functions. 53 M. tuberculosis, which render canonical drugs that specifically
KEY CONCEPtS target bacterial molecular processes ineffective. A new approach,
termed host-directed therapy (HDT) aims to develop new drugs
How Might a Vaccine Work? or repurpose previously approved ones that are directed at host
55
molecular processes. Such approaches include monoclonal
Activation of innate immunity for instruction of appropriate acquired antibodies (mAbs) to neutralize cytokines, such as TNF-α or
immune responses (PRRs)
Activation of the appropriate array of T-cell populations IL-6, to abrogate tissue destructive inflammation, repurposed
T-cell secretion of appropriate cytokine combination use of licensed drugs, such as ibuprofen and verapamil, to
Efficient development of T-cell memory modulate inflammation and enhance antibiotic effectiveness,
Efficient activation of antibacterial effector mechanisms respectively, and use of immunostimulatory natural molecules,
Best case scenario: sterile pathogen eradication such as vitamin D 3 to enhance bacterial killing by xenophagy.
Second best case scenario: driving the infection “deeper” into latency, These approaches range from preclinical and early-stage clinical
thus efficiently preventing reactivation of disease
development to late-stage clinical development and offer promise
to shorten the traditional duration of therapy.
Regulatory T Cells It is being increasingly recognized that the interaction between
Intracellular bacteria can cause detrimental inflammation and intracellular bacteria and the immune system is not of the “all
tissue damage, for example, as a result of IFN-γ- and TNF- or nothing” type but is instead a “continuous struggle.” This
α-mediated Th1 responses. Under normal circumstances, control realization has far-reaching implications for preventive and
mechanisms are in place to limit immunopathology. Such therapeutic strategies against intracellular bacterial infections.
countermeasures are elicited as part of the ongoing immune First, vaccination against intracellular bacteria has not yet been
response during infection. The main cytokines that limit inflam- effected satisfactorily because of the involvement of several distinct
mation and control IFN-γ production are IL-10 and TGF-β. T-cell subsets with different modes of stimulation and activity
Although macrophages and DCs produce these cytokines, their profiles. Second, chemotherapy has frequently proven to be
main producers are Tregs, which are the prime cells involved in suboptimal for the sterile eradication of bacteria hidden in cellular
immune regulation. Natural Tregs are responsive to IL-2 because niches. A better understanding of the complex crosstalk between
of high constitutive CD25 expression and are characterized by cytokines, T lymphocytes, macrophages, and infected host cells
54
expression of the transcription factor FOXP3. Expansion of will no doubt directly promote the development of improved
Tregs appears to be both antigen dependent and antigen inde- control measures. 55
pendent. In addition, Tregs selectively express TLRs and can be
activated, for example, by LPS and possibly other TLR ligands. ACKNOWLEDGMENTS
This makes their immediate activation during bacterial infection
a probable scenario. Although Tregs limit CD8 T-cell responses We are grateful to Mary Louise Grossman for excellent assistance
in experimental listeriosis, their general role in infections with and Diane Schad for the figures.
intracellular bacteria has not been fully elucidated. Suppression
of T-cell responses and anergy have been clinically documented Please check your eBook at https://expertconsult.inkling.com/
for TB and leprosy. Although Treg functions can limit detrimental for self-assessment questions. See inside cover for registration
T-cell responses and immunopathology, they can also prevent details.
elimination of bacteria, and hence are likely a key factor in
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