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Taking the ‘X’ out of histiocytosis
By Kenneth McClain, M.D., Ph.D.
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Dr. Kenneth McClain
participated in a bike trip more grueling than the Tour de
France to benefit LCH
research and raise awareness.
Read more about his incredible
ride. |
Many of us have learned about Histiocytosis X, eosinophilic granuloma, and
the several other
eponyms for what is now known as Langerhans cell histocytosis (LCH).
Over 30 years ago, Christian Nezelof and his
colleagues identified the Birbeck granules by electron
microscopy in LCH biopsies and correctly concluded that these
were the same cells as those that line the dermal-epidermal
junction of the skin. These epidermal Langerhans cells serve as
the “distant early warning” part of the immune system. The gene
that codes the protein for these granules was cloned, and now we
have a specific antibody assay for Langerin (CD207). The cause
of LCH is still unknown, but a few glimmers of light on the
pathophysiology are emerging.
Cytokines that allow the growth
of Langerhans cells (LC) from stem cells and form the
communication network with lymphocytes and macrophages are
severely out of balance in LCH lesions. There is no comprehensive story yet,
but a few insights have been made in our laboratory and others.
First, several members of the tumor necrosis factor family of
cytokines are present at higher level lesions in LCH-affected
patients.[1] These proteins promote growth of LC and contribute
to the systemic symptoms of fever and weight loss in severely
affected infants. We found two leukocyte growth factors (Flt-3
ligand and M-CSF) at higher levels in the plasma of LCH patients
at diagnosis and decreasing amounts as they responded to
treatment.[2] There are increased numbers of immature cells
related to LC (myeloid dendritic cells) in their blood. This has
prompted us to propose that LCH may be more of a “systemic”
disease than a local phenomenon, and we have designed
experiments to test this hypothesis. Another growth factor found
at unusually high levels in biopsies from lesions in LCH
patients is IL-10, which is known to inhibit normal LC
development. Through experiments that measure gene expression of
individual LC from LCH patients compared to LCs from normal
skin, we found this cytokine and several related cytokines, to
be expressed at much higher levels in LCH lesions than normal
skin.[Figure 1]
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Figure 1. Expression of
Cytokine Genes in CD 1a Cells |
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Unraveling the complex interplay of
cell types
What does this mean? It seems there are conflicting forces “at
war” in LCH, such that some cytokines inhibit and others promote
growth and maturation. If we only had to deal with LCs, this
might be an easier condition to treat; however, there are
macrophages, lymphocytes, eosinophils, and other inflammatory
cells participating in the maintenance and promotion of these
lesions. We suspect that lymphocytes and macrophages are key
players, because they also contribute to the cytokine excesses.
“Who is on first and what is on second” is clearly a problem in
this disease. Hence, another effort in our laboratory is to
define the gene expression profile of lymphocytes and
macrophages in LCH lesions in order to unravel the complex
interplay of there varied cell types.
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The biology of LCH is a complex
mystery. My laboratory is dedicated to solving this mystery,
but we are in desperate need of fresh biopsy specimens. |
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Treating LCH
Where is the bedside? The first-line therapy for LCH remains
vinblastine and prednisone for many patients, but clinical
trials we are participating in ask new questions and seek
answers. For example, when considering the very sick infants
with liver, lung, spleen or bone marrow LCH, will the addition
of intravenous and oral methotrexate improve the cure rate for
this difficult-to-treat patient group? If these infants do not
respond to therapy by six to 12 weeks, they are immediately
switched to a very aggressive myeloid leukemia-like treatment usingcytosine arabinoside and cladribine (2-CdA).
We have seen remarkable involution of lung disease in one infant
referred for possible lung transplant, as well as in infants
with marked liver and spleen enlargement. Other treatments
targeting the abnormal cytokine environment are also being
investigated. We conducted a clinical trial using thalidomide
because it inhibits tumor necrosis factor, an agent
over-expressed in LCH.[3] Six of eight patients with skin or
bone LCH responded to this novel therapy.
Tackling a complex mystery
Sometimes the “bench” or research side of a disease is the
clinical study itself. For the past two decades, several
worldwide clinical trials have been conducted to improve
treatment of LCH. Through the unique data base established by
the Histiocyte Society, long-term outcomes of patients with
specific manifestations of LCH can be tracked. It is known that
diabetes insipidus is a complication of LCH in roughly 20
percent of patients. Recently, it has become clear that 40
percent of patients with lesions in the orbit, mastoid, or
temporal bones will develop this complication unless treated
with velban and prednisone for at least six months.[4] Even with
this treatment, 20 percent will develop D.I. Dr. Nicole Grois
and her colleagues in Vienna have discovered that of patients who
develop D.I. 50 percent will have anterior pituitary hormone
deficits within 15 years and 50 percent will develop some type
of brain lesion.[5] These brain lesions may be masses or
infiltrations of the cerebellum, pons and basal ganglia that
lead to dysarthria, dysmetria, and learning difficulties. We are
in the process of developing a clinical trial for treatment of
these patients with cytosine arabinoside to prevent such late
effects
The biology of LCH is a complex
mystery. My laboratory is dedicated to solving this mystery, but
we are in desperate need of fresh biopsy specimens. I encourage
all surgeons and clinicians who see any patient with a lytic
bone lesion or lymphadenopathy, or who might diagnose or follow
an LCH patient to contact me early in their workup so that we
can seek permission to obtain tissue for biologic studies. This
investigative and clinically-relevant work has been approved by
the local Institutional Review Board (IRB) and recently was
awarded funding from the National Institutes of Health
(NIH).
Kenneth McClain M.D., Ph.D., is a pediatric
hematologist/oncologist with Texas Children’s Cancer Center® and
professor of Pediatrics at Baylor College of Medicine.
References
McClain KL , Cai Y-H, Hicks J,
Peterson LE,Yan X-T, Che S, Ginsberg SD Expression profiling
using human tissues in combination with RNA amplification and
microarray analysis: assessment of Langerhans cell histiocytosis.
Amino Acids 2005;28:279-290.
Rolland A, Guyon L, Cai Y-H,
Banchereau J, Palucka K, McClain KL. Increased blood myeloid
dendritic cells and DC-poietins in Langerhans cell histiocytosis.
J Immunology 2005;174:3067-71
McClain KL, Kozinetz C.
Treatment of Refractory Langerhans Cell Histiocytosis with
Thalidomide. A Phase IIA study. Pediatric Blood/Cancer 2005 Dec
6 Epub ahead of print
Grois, N, Potschger, U, Prosch,
H, et al. Risk factors for diabetes insipidus in langerhans cell
histiocytosis. Pediatr Blood Cancer 46 (2): 228-33, 2006.
Mittheisz E, Seidl R, Prayer D,
et al. Central Nervous System-Related Permanent Consequences in
Patients with Langerhans Cell Histiocytosis. Pedatr Blood
Cancer. Epub ahead of print.
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