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Arch Immunol Ther Exp, 2005, 53, 143–147 in chronic lymphocytic leukemia: lessons from Crohn’s disease and the therapeutic potential of bupropion to lower TNF-α Richard E. Kast1 and Eric L. Altschuler2
1 University of Vermont, Burlington, VT 05401, USA2 Mt. Sinai School of Medicine, New York, NY 10029, USA Source of support: self financing
Crohn’s disease and B cell chronic lymphocytic leukemia (CLL) share a common link intheir pathologic mechanisms. Lymphocytes in both diseases fail to undergo apoptosis anddie properly. That failure is partly due to increased signaling by tumor necrosis factor(TNF)-α, and their respective pathologies directly follow from this apoptosis failure.
Bupropion is a commonly used generic antidepressant in clinical use for over a decade,and early evidence indicates it lowers TNF levels. This paper suggests the use of bupro-pion in CLL to lower TNF levels, which may thereby slow CLL disease course.
apoptosis • bupropion • chronic lymphocytic leukemia • Crohn’s disease • etanercept • inflam-mation • infliximab • lymphocyte • treatment • TNF-α CLL – B cell chronic lymphocytic leukemia, cAMP – cyclic adenosine monophosphate, CD – Crohn’s disease, TNF – tumor necrosis factor α, NF-κB – nuclear factor kappa B.
http://www.aite−online/pdf/vol_53/no_2/7150.pdf Richard E. Kast, M.D., University of Vermont, 2 Church Street, Burlington, VT 05401, USA, e−mail:[email protected] or Eric L. Altschuler, M.D. Ph.D., Mt. Sinai School of Medicine, 1425 Madison Ave., Box 1240, New York, NY 10029, USA, e−mail: [email protected] Arch Immunol Ther Exp, 2005, 53, 143–147 INTRODUCTION
-TNF antibody infliximab lowers CD activity (ref.25,and many others), and this has been shown to occur This short paper has a simple story to tell: Crohn’s by increasing intramural lymphocyte apoptosis7, 11, 29.
disease (CD) and B cell chronic lymphocytic In initial, uncontrolled clinical use, bupropion seems leukemia (CLL) share a common link in their patho- to be an effective treatment of CD13, 14, 15. logic mechanisms. Lymphocytes in both diseases failto undergo apoptosis and die properly. That failure is This paper presents the argument that CLL might be partly due to increased anti-apoptosis signaling by ameliorated by bupropion in a parallel fashion tumor necrosis factor (TNF)-α. The core feature of although, we expect, less thoroughly than CD because the two pathologies, though they are clinically quite there are many other derangements in CLL beyond different, directly follows from this TNF-mediated TNF dysregulation. CD is a simpler disease than CLL.
apoptosis failure. Bupropion is a commonly usedgeneric antidepressant in worldwide clinical use in Etanercept is a soluble, TNF R2-based protein for the treatment of depression for over a decade, and use in the treatment of rheumatoid arthritis.
early evidence indicates it may lower TNF levels.
Infliximab is effective in the treatment of CD25, but Bupropion, in initial clinical use, seems to reliably etanercept has no activity in CD amelioration25, 29, lower CD activity. This paper suggests the use of which corresponds to observations that infliximab, bupropion in CLL to lower TNF levels and, thereby, but not etanercept, induces apoptosis in lamina pro- pria lymphocytes from patients with CD7, 29.
An essential link in the development of overt CD iscreated when TNF becomes a survival signal for lam- TNF is a circulating 17 kDa signaling molecule syn- ina propria lymphocytes to a pathological degree, this thesized by a wide range of cells, reviewed in refer- paper suggesting by a manner and mechanism as that ences18, 31. It is also found fixed within the outer cell in CLL. A TNFR1-to-TNFR2 switch of predomi- membrane in a 26 kDa transmembrane form. Both nance on the lamina propria lymphocyte surface is forms are active, potent signaling molecules. Some seen in CD10, 11 corresponding to a switch from functions overlap (can be performed by both forms), TNF-induced apoptosis (TNFR1 prominent) to while some are preferentially performed by one or a TNFR2 (pro-survival, anti-apoptotic, nuclear factor the other form. All soluble 17 kDa TNF derives from proteolytic cleavage of the transmembrane form.
TNF is thought to act only by ligation to one of the Why does etanercept not help in CD? We suggest two known specific receptors, R1 or R2. TNF effects that by further shifting the signaling weight to are supremely pleiotropic, which is essential to the TNFR2 through a relatively selective inhibition of function of many systems. Although considerably sTNF and a relatively weak or non-inhibition of more complex than this, TNF function can be rough- tmTNF signaling, the core problem is not redressed.
ly categorized as apoptosis triggering (frequently, but Bupropion may down-regulate TNF synthesis gener- not exclusively, through R1) and anti-apoptosis, pro- ally, providing a balanced TNF-signaling reduction, -inflammatory signaling (frequently, but not exclu- without shifting the TNFR1/TNFR2 relative weight- sively, through R2)18, 31. Physiologically, these two ing. If this proves to be correct, TNF survival signal- functions can be and often are simultaneously initiat- ing to the problematic persisting lamina propria lym- ed by TNF, although apoptotic or anti-apoptotic phocytes would be reduced, allowing them to die off and not perpetuate the mutually reinforcing cycle ofmucosa breakdown outlined below.
The monoclonal antibody infliximab, by binding Recent advances in our understanding of how the more to tmTNF than etanercept does2, 7, 29, can pre- superficial erosions of the gut wall mucosa (aphthae) vent TNF anti-apoptosis signaling via TNFR2, thus occur in CD have given clues to a better treatment of facilitating apoptosis in the problematic lamina pro- some cancers. The documented apoptosis-inhibiting effects of TNF in the lamina propria lymphocytescontribute strongly to the aphthae generation in CD7, Lamina propria lymphocytes have many housekeep- 10, 29. The relevant lymphocytes do not die off proper- ing functions, one of which is defense-early-warning ly and, by persisting, continue generating inflamma- signaling of antigenic attack (predominantly micro- tory signals that eventually erode the mucosa.
bial). In CD these lymphocytes mediate a protracted Lowering TNF function with the monoclonal anti- immune/inflammatory response unwarranted by R. E. Kast et al. – TNF-α in chronic leukemia commensurate luminal aggression7, 10, 11, 29. The resulting overly exuberant response damages other-wise healthy and well-functioning nearby mucosa.
As has been noted for other B lymphocyte malignan- Mucosal damage provides a protective barrier breech cies, for example multiple myeloma, the malignant that is taken advantage of by lumen bacteria and cells of CLL show chronically and tonically activated viruses; also food antigens gain access to the gut wall NF-κB21. In vitro apoptosis of CLL cells is invariably substance. This provides additional antigenic stimuli, preceded by NF-κB activation loss6. The activation correctly perceived by lamina propria lymphocytes.
and transcription of multiple anti-apoptosis genes The resulting immune response extends mucosal consequent to NF-κB activation is seen in CLL34, and damage. Thus the aphthous lesion of Crohn’s is built TNF is one of the primary activators of NF-κB18, 31, 34.
up by a mutually reinforcing feedback cycle betweenluminal aggression breech of the gut mucosal barrier and the over-exuberant response to it mediated byanti-apoptotic TNF signaling on lamina propria lym- The malignant lymphocytes in CLL bear TNF recep- tors that are heavily weighted or completely restrict-ed to R227, 28, 32. Note the parallel shift to R2 seen in TNF AND CLL
lamina propria lymphocytes in CD10, 11 mentionedabove.
CLL is a prime example of an indolent cancer char-acterized by abnormally low apoptosis rather than CONCLUSIONS
increased mitosis16, 19. Although multiple apoptosis-inhibiting factors other than TNF have been identi- Thus the malignant B lymphocytes of CLL are fied in CLL (examples in ref.16, 19), much data indi- exposed to an abnormally TNF-enriched environ- cate that excess TNF function in the bone marrow is ment in CLL. One of the curiosities, which is simul- a central mediator of the malignant lymphocytes’ taneously a huge hint into its pathogenic mechanism, is the finding of above-normal in vitro apoptosis ofCLL lymphocytes yet abnormally low in vivo apopto- sis12. It is likely that precisely this TNF-enriched bonemarrow environment is what accounts for the All CLL patients were seen to have PHA-stimulated reduced in vivo apoptosis, and deprivation of that peripheral blood culture TNF levels greater than con- TNF-enriched environment is what allows apoptosis trols’ 3. Circulating TNF levels in CLL patients are higher than normal1, 5, 8 and levels increase with advanc-ing disease stage1, 8. Higher TNF levels correlate with A recently completed phase II trial of theophylline in shorter survival8. Aggressive CLL shows higher circu- CLL has shown evidence of a weak but clear activity lating TNF levels than do less aggressive forms23.
in slowing disease progress33. Theophylline, as a weakphosphodiesterase inhibitor, increases intracellular cyclic adenosine monophosphate (cAMP), thus low-ering TNF synthesis. This work shows proof-of-prin- A greater percentage of circulating and bone marrow ciple. Other more specific phosphodiesterase B lymphocytes immunostain positive for TNF than inhibitors (of the IV isoform), such as rolipram, have normal ones4. The malignant B cells themselves syn- shown in vitro pre-clinical apoptosis induction in lym- thesize increased TNF in vivo17.
Already in 1993, TNF was recognized as a significantgrowth factor in CLL and a suggested target for ther- Increased T lymphocyte synthesis occurs in peripher- apeutic inhibition30. Even then the inverse relation- al T cells late in CLL upon in vitro stimulation9, 23.
ship between intracellular cAMP and TNF was rec- CD2+ lymphocytes (comprising NK cells and 90% of ognized, as was in vitro CLL cell proliferation inhibit- circulating T cells) from CLL patients had higher in ed through increased cAMP reduction of TNF30.
vitro stimulated TNF synthesis than did normals20.
T cells show upregulated, increased TNF in the bone marrow of CLL4, 17 and circulating T cells show upreg-ulated TNF synthesis in CLL4. Again, TNF-positive Also of concern is the potential for negative interac- circulating T cells are more numerous in advanced tion between bupropion or any other TNF synthesis- stages of CLL compared with earlier stages4.
-lowering maneuver, for example by thalidomide, Arch Immunol Ther Exp, 2005, 53, 143–147 during rituximab treatment. Rituximab is a mono- treatment with TNF-elevating agents14 prior to and clonal antibody to CD20, a surface antigen found on during treatment with these CD20-targeted treat- the malignant lymphocytes in some CLL cases. CD20 ments, followed by anti-TNF treatments, for example antibody treatment of CLL has shown some benefit22.
There is evidence that lymphocyte CD20 expressioncan be upregulated by TNF and down-regulated in If our currently ongoing clinical success with bupro- the absence of sufficient TNF24. Therefore treatment pion treatment of CD holds up in double-blind place- with rituximab should be temporally separated from bo-controlled trials, we think bupropion might prove TNF suppression with bupropion. These same cau- to be considerably more potent in TNF synthesis sup- tionary concerns should also apply to the radioactive pression than theophylline, and would therefore be anti-CD20 treatments Bexxar and Zevalin.
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