Asia Pac J Clin Nutr 2008;17 (2):187-193 187

Review

HPV-induced recurrent laryngeal papillomatosis:

rationale for adjuvant fatty acid therapy

Louise Louw PhD and André Claassen MMed FCORL

Department Otorhinolaryngology, University of the Free State, Bloemfontein, South Africa.

The course of human papilloma virus (HPV)-induced recurrent laryngeal papillomatosis (RLP) is variable and
unpredictable. Some patients experience spontaneous remission, while others suffer from aggressive growth
with dire consequences. Unfortunately, HPV DNA can persist in mucosa after treatment and can be reactivated
under immunosuppressive conditions. For this reason, these benign tumors are notoriously recurrent. Better un-
derstanding of lipid-driven signaling pathways during tumorigenesis and immune responses in RLP patients can
contribute to improve therapeutic approaches in an attempt to obviate this disease. Based on a mountain of evi-
dence in the literature that concerns the immunomodulatory potential of certain FAs, it is clear that there is a ra-
tionale for adjuvant FA therapy (concurrent application) in the management of RLP. Of particular importance
for immune surveillance is that the Th1 pathway in RLP is down-regulated and it is advocated that conjugated
linoleic acid (CLA) and eicosapentaenoic acid (EPA) have the ability to restore the Th1/Th2 balance. Therefore,
it is proposed that adjuvant FA therapy with CLA and EPA must be included in the therapeutical regime of RLP,
since they are considered excellent anti-viral and anti-tumor agents to improve immune conditions and disease
outcome. Immunocompetence plays a pivotal role in the clinical course of RLP and, hence, a new direction with
adjuvant FA therapy may be the key to prevent recurrence of this disease.

Key Words: Benign tumors, laryngeal papillomatosis, therapeutic rationale, adjuvant fatty acid therapy,
nutritional immunomodulation

INTRODUCTION toxic T lymphocyte function expression, can be up-

Human papilloma virus (HPV)-induced recurrent laryn- regulated by immunomodulatory fatty acids (FAs).3-7
geal papillomatosis (RLP) poses a risk of morbidity and This mini-review emphasizes the paramount importance
mortality. Hoarseness is an early sign and airway ob- and influence of fatty acids (FAs) on immune surveil-
struction a later life-threatening sign. Despite multiple lance in RLP patients and how adjuvant FA therapy can
treatment modalities, this disease is still hallmarked by be applied to improve immunocompetence. A body of
recurrence that necessitates repeated surgery as the main- research information that validates the beneficial use of
stay treatment. The severity of this disease varies due to specific FA agents in the therapeutic regimes of different
unpredictability of clinical remissions and recurrences. tumor and cancer entities is discussed in support of our
The viruses involved (mostly HPV6 and HPV11) are held proposal for adjuvant FA therapy with conjugated linoleic
in a subclinical state in exposed individuals by a compe- acid (CLA) and eicosapentaenoic acid (EPA), with or
tent immune system, but are reactivated under immuno- without appropriate drugs after surgery, for the manage-
suppressive conditions and, hence, recurrence of RLP ment of RLP.
prevails, especially among young children.1,2
Lipid-driven membrane-to-nucleus signaling pathways CLINICAL COURSE OF RLP AND TREATMENT
are responsible for cellular changes that may have pro- DIFFICULTIES
found influences on cell growth that manifest in laryngeal HPV-induced laryngeal papillomatosis remains a chal-
papillomatosis and the immune defenses of patients with lenging disease for surgeons, since it can be notoriously
RLP. Both cellular and antibody (humoral) immune re- recurrent and necessitates repeated laryngoscopy and sur-
sponses may be involved and the patient’s immunocom- gical debulking to maintain a patent airway until the dis-
petence may influence the clinical course of the disease. ease regresses spontaneously. Among potential complica-
Among T lymphocytes, cytotoxic T lymphocytes (CD8+ tions, spread to the lungs is considered the most severe
cells) and T helper cells (CD4+ cells) play a central role complication, owing to inaccessibility. Recurrence of this
in immune surveillance and virus elimination. Among T
helper cells, a Th1/Th2 balance exist that regulates cyto- Corresponding Author: Prof Louise Louw, Department of
kine subsets for cell-to-cell communication and func- Otorhinolaryngology, Health Sciences, UFS, Bloemfontein, SA
Tel: + 27 51 4053493; Fax: + 27 51 4053102
tional integration of the immune system. Of interest is
Email: [email protected]
that deficiency of the Th1 cytokine interleukin-2 (IL-2), Manuscript received 6 Febuary 2008. Initial review completed
responsible for lymphocyte clonal expansion and cyto 12 May 2008. Revision accepted 15 May 2008.
188 L Louw and A Claassen

tumor is ascribed to the fact that HPV DNA can persist in driven signaling pathways during, respectively, tumori-
adjacent, normal-appearing mucosa after surgical treat- genesis and immune responses. According to the litera-
ment. Several adjuvant therapies have been advocated in ture, excessive dietary LA and SFA intakes are associated
the past and among them are interferon, cidofovir, imi- with inflammatory conditions and tumorigenesis, as well
quimod, indole-3 carbonyl, ribavirin, and photodynamic as Th1 inhibition and immunodeficiency.13 Of particular
therapy. Cidofovir is being used increasingly to treat importance is that transcription factors involved in these
benign RLP caused by HPV types 6 and 11, whilst imi- signaling pathways, including nuclear factor-kappa beta
quimod is also considered an extremely useful addition to (NF-κβ) as the central mediator of the immune system,
the armamentarium of HPV therapies. As with surgical are targets that can be regulated with FA therapy and phy-
management, viral persistence occurs with these adjuvant tochemicals, such as indole-3 carbinol.14-17 The impor-
therapies.1,2 Failure of the immune system (both cellular tance of NF-κβ activity to orchestrate patient immuno-
and humoral components, to successfully control HPV- competence can not be underestimated. Feedback
infected cells contributes to RLP and the immunocompe- mechanisms exist, whereby, NF-κβ is activated by
tence of these patients may influence the clinical course growth factors, cytokines, free radicals and oncogenes
of the disease. The potential use of HPV testing and vac- and, in turn, NF-κβ stimulates growth factors, cytokines
cines to prevent or combat HPV infection holds the key to and oncogenes (Fig 1).18-20 Therefore, NF-kB controls
optimal management of this potentially devastating dis- proliferation, apoptosis and immunity, all crucial steps on
ease. Preclinical vaccine studies for papillomas based on which therapy is based. It is suggested that overlapping
oncogene peptides or proteins, DNA plasmids and differ- HPV expression (E6 protein of low risk HPV types 6 and
ent viral vectors are documented, all with shortcomings 11) and NF-κβ in the cell nucleus has the potential to
and benefits.8-10 A clinical trial with HspE7, a wide spec- immortalize cells by degrading the tumor suppressor p53
trum vaccine that targets papillomas, reduced disease oncogene, abrogating survival protein p21, and enhancing
recurrence in laryngeal papillomas, but lacked a placebo anti-apoptotic Bcl-2 in RLP patients.21 It is also conceiv-
group. 9 An appropriate vaccine for laryngeal papilloma- able that prolonged disease conditions can eventually
tosis is still awaited and, until then, it seems imperative to down-regulate cytokines and lymphocytes that may lead
properly address cytotoxic T lymphocyte function. to immunodeficiency in RLP patients. Modulation of
membrane FA compositions for manipulation of abnor-
LIPID AND IMMUNE STATUS OF RLP PATIENTS mal signaling pathways to prevent tumorigenesis and
From our preceding lipid studies with RLP patients,11, 12 it immunodeficiency is a therapeutic tool that is currently
is evident that enhanced dietary linoleic acid (LA) and receiving renewed interest. In the case of RLP patients
saturated fatty acids (SFAs) are responsible for lipid where, among other factors, NF-κβ and the anti-apoptotic

Figure 1. The diagram illustrates lipid drive tumorigenesis and immune responses by linoleic acid and saturated fatty
acids, and the central role that NF-kB plays during these two main events. The cellular arm of the immune response
plays an important role during recurrent laryngeal papillomatosis and the up-regulation of interleukin-2 (IL-2) and
consequently also cytotoxic T cells (CD8+ cells) is suggested.
 Laryngeal papillomatosis and adjuvant fatty acid therapy 189

gene Bcl-2 are up-regulated,21, 22 the beneficial therapeu- with PPAR target therapy is suggested.28 However, it is
tic use of FA therapy needs to be evaluated. argued that FA therapy, modulation of membrane FA
compositions with those FAs that are ligands for specific
THE IMPORTANCE OF IMMUNOCOMPETENCE PPAR family members to redirect signalling pathways,
TO COMBAT RLP might be on the long term a more appropriate approach.
It is imperative to improve the immunocompetence of At this point in time, a balance between PPARγ and
RLP patients, since immunodeficiency may hamper the PPARα, associated with cell proliferation and inflamma-
clinical course of the disease. For immune surveillance tory conditions, and PPARδ/β, associated with apoptosis,
(the body’s ability to detect and destroy tumor cells) the is considered important. Research revealed that PPARδ/β
cellular arm (Th1) of the immune response is important as has the ability to induce apoptosis, but when over-
Th1 pathways typically produce activation of cells that expressed it suppresses apoptosis. Based on laboratory
include cytotoxic T-lymphocytes. T lymphocytes produce studies, CLA and EPA can activate PPARγ and PPARα
cytokines and play a critical role in defining the type and and, thereby, tilts the scale in favor of apoptosis.29,30 In
magnitude of the immune response. Depending on the the case of RLP, high LA and palmitic acid (PA) levels
mode of activation, T-lymphocytes differentiate into ei- are apparently responsible for, respectively, a mitogenetic
ther helper Th1 or Th2 cells (CD4+ cells), or become driven stimulus and the apoptotic resistance of papilloma
cytotoxic T lymphocytes (CD8+ cells). The Th1 cell cells.11,12 The potential of CLA and EPA to re-direct sig-
produces primarily interleukin-2 (IL-2), interferon naling pathways and, thereby, prevent RLP needs to be
gamma (IFN-γ) and tumor necrosis factor -α (TNF-α), explored.
resulting in enhanced cell-mediated or cytotoxic re-
sponses. The Th2 cell produces IL-4, IL-5, IL-6 and IL- RATIONALE AND PROPOSAL FOR ADJUVANT
10, generating a humoral or anti-body-mediated immune FATTY ACID THERAPY
response. According to available information, the HPV- There is compelling evidence available from in vitro and
11 E6 protein appears to be the dominant inducer of cyto- in vivo studies that demonstrate the ability of CLA to
kine expression that favors cytokine Th1 responses in modify immune responses and the impact it has on cyto-
RLP.23 Research confirmed that IL-2 expression is de- toxic T lymphocytes to eliminate virus particles or to con-
creased, while IL-10 expression is increased in RLP pa- trol/ ameliorate virus infection.15 Important findings from
tients.5, 23 In the case of cell-mediated responses it be- a pig model with virally induced immunosuppression
came evident that CD8+ cells are potent mediators of revealed the ability of CLA to stimulate the T-cell lym-
viral clearance, but during chronic infections CD4+ cell phocyte response and enhance cellular immunity by
help is required to sustain antiviral CD8+ cell activity for modulating phenotype and effector functions of CD8+ T-
immune attack in RLP patients.3,4 As far as the humoral cells, involved in both adaptive and innate immunity.3,4 It
response is concerned, deficiency of immature B cells and is also evident that two CLA isomers (cis-9, trans-11 and
an imbalance between immunoglobulins (Ig) with en- trans-10, cis-12) exert distinct effects on T lymphocyte
hanced IgE is implicated in RLP.24 It is predicted that up- populations and immunoglobulin subclasses.15 Of impor-
regulation of IL-2 and lymphocyte counts/function may tance is the fact that CLA has the potential to up-regulate
improve the immunocompetence of RLP patients. IL-2 production and to improve cytotoxic T lymphocyte
function, as well as the potential to down-regulate IgE
MODULATION OF IMMUNE SYSTEM BY SPE- and to improve B lymphocyte maturation.15 Evidence for
CIFIC FATTY ACIDS the efficacy and safety of CLA administration in humans
Clinically relevant to RLP patients are those FAs with is being steadily strengthened by results from animal
anti-viral and immunomodulatory potential that are advo- toxicology tests, as well as clinical trials. Currently, mix-
cated to be useful in preventing and/or reversing some of tures (mostly 50:50) of CLA products (cis9, trans11-18:2)
the side effects of retroviral drugs. Among them, conju- are used for inflammatory conditions.15,27,31 Interestingly,
gated linoleic acid (CLA), derived from dairy products CLA could be particularly beneficial for immunocom-
and ruminant meats, and eicosapentaenoic acid (EPA), promised individuals who are slow to or low responders
derived from fish, and are highly acclaimed.15,16,25,26 to vaccination.15 A substantial body of work also indi-
CLA (isomers of LA) protects against tumorigenesis, cates the immunomodulatory potential of n-3 PUFAs that
unlike LA that stimulates tumorigenesis, and is currently improve quality of life in diseases currently considered to
widely explored.26 CLA has the potential to manipulate be Th1 or Th2 associated.7 The impact of n-3 PUFAs lies
the AA cascade, modulate the immune system and ame- in their ability to prevent inflammatory conditions and,
liorate viral infection.15 Although the safety and effec- thereby, modulate immune responses.32,33 Interestingly,
tiveness of CLA for clinical use is already determined, in vivo research revealed that dietary CLA-
there is still ongoing research to clarify the beneficial use supplementation delayed the onset of inflammatory bowel
of different isomers and their mixtures for specific condi- disease by down-regulation of eicosanoids and up-
tions or diseases.27 The anti-inflammatory role of EPA to regulation of PPARγ, whereas n-3 PUFAs accelerated
manipulate the arachidonic acid (AA) cascade and to im- colonic regeneration and clinical remission by activating
prove membrane FA compositions for normal cell func- PPARδβ.34
tion is well established.16 From the preceding information it is clear that there is
Specific FAs, ligands for peroxisome proliferator- a rationale for adjuvant FA therapy in the management of
activated receptors (PPARs), drive tumor and immune RLP. CLA and EPA, to prevent tumour growth, elimi-
signaling pathways and, interestingly, a new direction nate HPV particles or to control / ameliorate HPV infec-
190 L Louw and A Claassen

tion and to improve immune defences is proposed. Adju- CLA and EPA after surgery, with or without drugs, to
vant FA therapy, concurrent application to enhance anti- eliminate the virus and to improve patient well-being and
viral drugs or alone to replace drugs, after surgery to im- disease outcome for RLP management need to be evalu-
prove immune defences and disease outcome is proposed. ated. The transition of experimental findings to clinical
application is hampered by a lack of randomized clinical
DISCUSSION trials with long-term follow-up studies. Available re-
Based on a mountain of evidence in the literature (in vitro search findings presented in this mini- review serve as a
and in vivo animal and human studies) that FAs can in- strong incentive for intervention trials that will test the
hibit cell proliferation, induce apoptosis, improve im- effect of recommended adjuvant FA therapy in the man-
mune responses and even enhance the impact of other agement of RLP patients.
treatment modalities,35-59 it is suffice to say that there is a
rationale for adjuvant FA therapy in the management of ACKNOWLEDGMENTS
different tumor and cancer entities. Depending on etio- This study was supported with UFS funds.
logical causes and the clinical interventions required,
there are those FAs advocated to: eliminate bacteria and AUTHOR DISCLOSURES
viruses or ameliorate bacterial or viral infections; protect Louise Louw and André Claassen, no conflicts of interest.
against smoke particles and oxidative stress, regulate and
redirect enzymes where interference with essential fatty REFERENCES
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 Laryngeal papillomatosis and adjuvant fatty acid therapy 193

Review

HPV-induced recurrent laryngeal papillomatosis:

rationale for adjuvant fatty acid therapy

Louise Louw PhD and André Claassen MMed FCORL

Department Otorhinolaryngology, University of the Free State, Bloemfontein, South Africa.

人類乳突病毒誘導復發喉頭乳瘤：脂肪酸輔助治療之
理論基礎

人類乳突病毒誘導復發喉頭乳瘤(RLP)的發生是多變的且不可預料的。有些病
人的症狀會自動減輕，但有些病人則長出大瘤導致嚴重後果。不幸地，接受
治療後，人類乳突病毒之 DNA 仍可持留在黏膜中且在免疫抑制的情況下，還
會被活化。因此這些良性瘤會猖狂地不斷復發。了解 RLP 病人在致瘤過程和
免疫反應中的脂質訊號路徑有助於改進此疾病的治療方法。既然脂肪酸的免
疫調節功能已有佐證如山的文獻證據，顯然應用在 RLP 病人也是有合理的根
據。在 RLP 中，Th1 路徑被向下調節，而共軛亞麻油酸(CLA)和二十碳五烯
酸(EPA)被認為能夠恢復 Th1/Th2 的平衡。自從它們被認為是傑出的抗病毒和
抗腫瘤劑而能改善免疫情況和疾病結果後，含有 CLA 和 EPA 的脂肪酸輔助治
療就被提議包含在 RLP 的療程內。臨床上 RLP 病人的免疫能力扮演著一個重
要的角色，因此以脂肪酸輔助治療的新方向可能成為預防疾病復發的重要關
鍵。

關鍵字：良性瘤、喉頭乳瘤、治療理論基礎、脂肪酸輔助治療、
營養免疫調控