06; aline 2
takenes, foal trit assoeque
2007 Elsevier B.V. All rights reserved.
counter. The author terms this cognitive mode thinking with-
of JC virus (JCV), the causative agent of PML, leading tounrestrained viral replication and spread of infection to central
mediated immunosuppression caused PML. However, several
effect, or a direct consequence of the mechanism of thera-peutic action? The answer to this question is important fordefining how MS drug development will proceed. If PMLwas a unavoidable result of inhibiting leukocyte trafficking,
encesnervous system (CNS) glia, with the catastrophic consequenceof PML. A recent editorial stated Therefore, it appears likelyout thinking. While granting Gladwell that blink thinking isan intriguing phenomenon, it is also valid to consider cir-cumstances in which these instantaneous impressions need tobe revisited, to arrive at a correct apprehension of a complexsituation. The relationship between natalizumab administra-tion and progressivemultifocal leukoencephalopathy (PML) isone such case. The blink view of this relationship is thatnatalizumab recipients lacked effective immunosurveillance
lines of evidence indicate that this conclusion is premature.Relevant considerations include effects of natalizumab onbone marrow physiology (quite apart from mechanisms forinhibiting inflammation) and the incompletely decipheredbiology of JCV infection. As we proceed beyond the blinkresponse, it seems apparent that more information is requiredto understand how PML occurred in natalizumab recipients.
Was PML in natalizumab recipients an off-target adverseA strange emotional state, equally composed of elationand despair, has been induced by progress and complicationsin the development of drug treatments for multiple sclerosis(MS) and other inflammatory disorders such as Crohn'sdisease [1,2].
In his new book Blink , Malcolm Gladwell argues infavor of the value of initial impressions, arrived at using onlythat information garnered in the first few seconds of an en-
summarized the situation by declaring that Bad things mayhappen when rescuers are turned back at the gates .
This type of blink thinking about natalizumab and PMLis logical: prior PML cases invariably arose in the contextof immunosuppression and natalizumab, which blocks 4integrins (including 41/VLA-4 and 47), had a powerfulanti-inflammatory effect in treating multiple sclerosis (MS)and Crohn's disease, so it seems plausible that natalizumab-Keywords: Integrin alpha4beta1; Monoclonal antibodies; Multiple sclerosis; Progressive multifocal leukoencephalopathy; JC virus; Immunologic surveillance;Demyelinating diseasesThinking without thinking
Neuroinflammation Research Center, Department of Neurosciences, The
Received 27 January 20Available on
The novel multiple sclerosis (MS) therapeutic natalizumab hasencouraging efficacy data led to expedited release in the United Statprogressive multifocal leukoencephalopathy (PML) in three clinicdistribution format. Aside from PML, natalizumab treatment was noPML in these individuals was mechanism-based, and was not a consa hypothesis to account for PML in natalizumab-treated patients.
Journal of the Neurological Scithat natalizumab, by preventing normal trafficking of lym-phocytes, led to unbridled JC virus replication, and
0022-510X/$ - see front matter 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.jns.2006.04.011bout natalizumab and PML
er Research Institute, The Cleveland Clinic Foundation, United States
ccepted 13 April 20062 May 2007
neurologists and their MS patients on a roller-coaster ride: initialllowed by suspension of dosing with the unexpected occurrence ofal participants. The drug was re-released in 2006, in a restrictedciated with opportunistic infections, suggesting the possibility thatnce of generalized immunosuppression. This commentary proposes
259 (2007) 5052www.elsevier.com/locate/jnsthen we must abandon this extremely promising avenue fortreating the vast majority of our patients, especially those
eurolowith early, mild disease and uncertain prognosis for disability. If PML was an off-target adverse effect, then leukocytetrafficking remains a valid therapeutic target.
One must first consider41/VCAM-1 interactions in theadult hematopoietic system, beyond those which supportinflammation. 41 is required for generating T cells and Bcells from bone marrow progenitors in adult mice, and forsome inflammatory lymphocyte trafficking but not for entryinto spleen, lymph nodes or intestinal epithelium . In adultmice with conditional, interferon-induced deletion of 4-integrin from hematopoietic cells, circulating cells showedlarge numbers of myeloid progenitors (for nearly one year),along with doubling in blood lymphocyte counts .Tellingly, there were 20% fewer B cell progenitors in marrow. Patients that received natalizumab exhibited elevatedbasophil, eosinophil and lymphocyte counts, with approxi-mately 5% showing circulating nucleated erythrocytes(Tysabri package insert). Natalizumab, unlike many otherleukocyte trafficking modulators, potently affects bonemarrow physiology by blocking 41/VCAM-1 interactions[6,810].
This finding may be pertinent for the biology of JCV innatalizumab recipients. Eighty percent of the population areJCV seropositive, with an unknown number harboringreplication-competent virus in renal tubular epithelial cellsand bonemarrow, and a smaller number harboring potentiallypathogenic virus. When PML occurs, JCV sequences in bonemarrow and blood, but not kidney or urine, strongly resemblethose in CNS, and carry tandem repeats in the transcriptionalcontrol region (TCR) that are required for replication in glialcells in vitro. Reactivated, pathogenic JCV is believed totransit to CNS through B lymphocytes or as cell-free virus. Therefore, effects of natalizumab on bone marrowphysiology, and B-cells in particular, may be pertinent forPML pathogenesis. It is conceivable that 4-integrin block-ade mobilizes JCV-infected cells from bone marrow storesand that poor control of viral replication occurs in infectedpre-B cells in the circulation, deprived of contact with bonemarrow stromal cells .
Natalizumab strongly suppresses inflammatory leukocytetrafficking intoCNS across parenchymalmicrovessels and alsoaffects immunosurveillance of the CNS. In particular, we andothers proposed that this function is carried out by cerebro-spinal fluid (CSF) memory T lymphocytes, whose entry intoCSF across the choroid plexus requires 41 , so thatCNS immunosurveillancewas clearly affected by natalizumab.During the time frame of clinical trials for MS and otherinflammatory disorders, natalizumab caused no other effectssuggesting immunosuppression: there were no increases incommon infections, nor other opportunistic infections, in morethan 4000 patient-years of clinical trial experience . Takentogether, the effects of natalizumab on bone marrow physi-ology, inflammatory CNS trafficking and CNS immune sur-veillance suggest that natalizumab-associated PML was
R.M. Ransohoff / Journal of the Nspecific to the 4-integrin target, perhaps augmented by theprolonged and remarkable efficacy with which it was blockedby natalizumab. Referring again to popular literature, thisconcurrence of effects may have represented a perfect storm with regard to pathogenesis of PML.
We suggest consideration of the following hypothesis:Natalizumab treatment led to PML beginning with its actiontowards infected bone marrow cells, by promoting theirpremature exit from the marrow, which both reduced theirability to control JCV replication due to non-physiologicaldeprivation of contact with bone marrow stroma and alsogave these infected cells access to all body compartments.These effects of natalizumab treatment, in combination withreduced surveillance and inflammatory trafficking to theinfected CNS, promoted PML pathogenesis. A natalizumab-induced spike of JC viremia in a Crohn's-disease patient may have represented proliferation of virus associated withcells that had been flushed from their physiological niche inthe bone marrow rather than uncontrolled JCV proliferationdue to immunosuppression. If this hypothesis is correct,agents that don't affect bone marrow will lack this com-plication, while those affecting bone marrow and lymphoidorgans (anti-CXCR4; anti-4 integrin; for example) mightrequire caution and surveillance. In conclusion, PML may beregarded as an off-target adverse effect, and it remainspossible to consider treating MS patients with agents thataddress leukocyte trafficking to the CNS.
Given the risk of PML and the potential benefits of thisclass of agents, we need to learn much more about JCVinfection without delay. It is not known how many healthyindividuals harbor pathogenic, reactivation-competent JCV, orwhether we can reliably detect such persons. It is imperative toclarify whether there is a reservoir of JCV in the CNS, as somehave suggested. The mechanism that generates tandem repeatsof JCV TCR elements is unknown. Relatively little is securelyknown about CNS immunosurveillance. It is important to staymindful of the benefits that natalizumab showed, and resolveto recapitulate the efficacy of this agent without its adverseeffects. Little, however, can be done, until we stop blink-ingand open our eyes.
 Ransohoff RM. Natalizumab and PML. Nat Neurosci 2005;8(10):1275.
 Multiple sclerosis woes. Nat Neurosci 2005;8(7):837. Gladwell M. Blink. Boston: Little Brown and Company; 2005. Berger JR, Koralnik IJ. Progressive multifocal leukoencephalo-
pathy and natalizumabunforeseen consequences. N Engl J Med2005.
 Steinman L. Blocking adhesion m