Immunologically mediated mucocutaneous diseases constitute a large group of oral mucosal disorders and are triggered by cellular or humoral responses directed against epithelial or connective tissues in a chronic, recurrent pattern. The treatment of these disorders should be directed not only toward relief from symptoms but also toward treating the underlying immune dysregulation, preventing recurrences, and preserving organ integrity and function

2. Immunomodulator
By
• Romissaa Aly Esmail
• Assistant lecturer of Oral Medicine, Periodontology,
Diagnosis and Dental Radiology (Al-Azhar University)

3. • Contents:
• Immunosuppressants in Oral Medicine
• Effects of Immunosuppressive
Medications on Mitochondrial Function
• Are immunosuppressive medications
associated with decreased responses to
routine immunizations

4. Immunologically mediated mucocutaneous
diseases constitute a large group of oral mucosal
disorders and are triggered by cellular or humoral
responses directed against epithelial or connective
tissues in a chronic, recurrent pattern.
They may be grouped under the following
categories:

6. The treatment of these
disorders should be directed
not only toward relief from
symptoms but also toward
treating the underlying
immune dysregulation,
prevent recurrences, and
preserve organ integrity and
function

7. The control of immune dysregulation can be
achieved by the use of immunomodulators,
defined as natural or synthetic substances that
help regulate or normalize the immune system
. In other words, they correct
immune systems out of balance, i.e.,
strengthen weak immune systems or
moderate over reactive immune
systems.
Immunomodulators may be further
classified into immunostimulants
and immunosuppressant

18. Biologics
Definition Biopharmaceuticals – biologics,
biologicals or biological agents (BAs) – are any
medicinal product manufactured in or extracted
from a biological source.
Biologics often target immunocytes or their
products, thus targeting specific steps in
proinflammatory pathways.

28. Figure 3. | Immunosuppressive agents
targeting T cell/B cell interaction,
plasma cell function, and complement-
mediated injury. APRIL, proliferation-
inducing ligand; BAFF, B cell–
activating factor; MAC, membrane
attack complex; TACI, transmembrane
activator and CAML interactor; TCR, T
cell receptor.

31. T-cells rely primarily on mitochondrial oxidative phosphorylation
pathways to generate ATP, although once activated, they also increase
their utilization of glycolysis, a process referred to as the “Warburg effect.”
Mitochondrial ATP production, Ca2þ uptake, and oxidative
phosphorylation ,all increase during T-cell activation and
mitochondria accumulate at the immune synapse during
antigen recognition

32. The long-term need for
immunosuppression raises the concern of
accumulating toxicities related to the use of
immunosuppressive medications
With current
immunosuppression
regimens, the median
survival of solid organ
transplants continues to
improve, with 1-y
survival exceeding 90%
for many organs.

33. It has been demonstrated that
some of these toxicities are due to
the effects of these medications on
mitochondrial function
For example, calcineurin
inhibitors have been
shown to cause
mitochondrial dysfunction
in kidney tubule cells,
potentially explaining the
nephrotoxicity commonly
caused by these
medications.

34. Kidney tubule cells treated with cyclosporine A
(CsA) show mitochondrial swelling, cytochrome c
release, and decreased mitochondrial membrane
potential, processes associated with apoptotic cell
death.

35. Mitochondrial dysfunction in endothelial cells
caused by CsA may also be responsible for the
development of hypertension associated with this
medication.
Furthermore, treatment of monocytes with
mycophenolate mofetil (MMF) and rapamycin has
been shown to induce apoptosis.
The effects of these medications on mitochondria
could help explain their toxicities in various tissues

36. The impairment of mitochondrial function by
commonly used immunosuppressive reagents
may impair T-cell differentiation and function
by decreasing energy production, producing
toxic ROS, and inducing apoptotic cell death.

37. Recent study shown T-
cells demonstrated
significant levels of
mitochondrial
depolarization after
treatment with
therapeutic levels of
MMF but not after
treatment with CsA,
tacrolimus, or rapamycin.

39. Fig. 1 e Effect of
immunosuppression reagents on
T-cell mitochondrial membrane
potential. Jurkat cells were
incubated for 24 h with
therapeutic and
supratherapeutic levels of
tacrolimus (FK506), rapamycin
(Rapa), cyclosporine A (CsA),
and mycophenolate mofetil
(MMF). After 24-h incubation,
cells were stained with DiOC6
and analyzed by flow cytometry
for mitochondrial membrane
depolarization as assessed by
decreased DiOC6 fluorescence.
(A) The percentage of cells with reduced DiOC6 staining is shown for each drug and
concentration in quadruplicate. The median and range of each data set is also shown. (B)
Representative flow cytometry after incubation with vehicle, 30 mM MMF, and TNF-a control. .
(B) Representative flow cytometry after incubation with vehicle, 30 mM MMF, and TNF-a
control.

40. (A) The percentage of
cells with increased
MitoSOX staining is
shown for each drug and
concentration in
quadruplicate. The
median and range are
also indicated. (B)
Representative flow
cytometry after
incubation with vehicle
control, 30 mM MMF,
and TNF-a control. C
Fig. 2 e Effect of immunosuppression reagents on T-cell reactive oxygen species (ROS)
production. Jurkat cells were incubated for 24 h with therapeutic and supratherapeutic levels
of tacrolimus (FK506), rapamycin (Rapa), cyclosporine A (CsA), and mycophenolate mofetil
(MMF). After 24-h incubation, cells were stained with MitoSOX Red and analyzed by flow
cytometry for ROS production as assessed by increased MitoSOX fluorescence.

43. Long-term immunosuppressive
medications are being used
more commonly for a variety of
medical conditions, including
immune-mediated diseases and
organ transplantation.
While these medications are
often necessary, they are
associated with an increased
risk of serious infections.

45. Conclusions:
Immunosuppressive therapy, particularly combination
regimens, may blunt response to influenza and
pneumococcal vaccinations.
To ensure the best chance of response, immunizations
should be administered prior to initiation of
immunosuppressive medications whenever possible.