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Hematopoietic stem cell transplantationwould be much more widely used in theclinic if graft-versus-host disease (GVHD)could be eliminated. In this condition,which afflicts 30–50% of all transplantrecipients, donor T lymphocytes attackrecipient cells in the skin, liver, gastrointesti-nal epithelium and elsewhere. Our under-standing of the trigger for GVHD is at bestimprecise, despite recent advances implicat-ing host antigen-presenting cells (APCs) inGVHD induction1,2.
In this issue, Merad et al. report that per-sistent host Langerhans cells, the major APCin the skin, are responsible for cutaneousGVHD3. Moreover, the authors report thatultraviolet (UV) irradiation can deplete hostLangherhans cells in mice; this treatmentleads to replacement with donor stemcell–derived Langerhans cells, which pro-tects against GVHD in the skin. Applicationof these findings to the clinic could havemajor implications for the prevention ofboth acute and chronic GVHD, and mayincrease the safety and applicability of stemcell transplantation.
T cells have long been known to be themajor cell type responsible for GVHD, but Tcell depletion of donor grafts decreases graftpotency and weakens the anti-tumor efficacy(when the transplant is employed in an anti-tumor setting). The recent findings that hostAPCs induce donor T cells to attack recipi-ent tissues1,2, and that APCs may also beneeded for trafficking of primed donor Tcells into host tissues4,5, presented a new
opportunity to prevent GVHD without Tcell depletion or blockade. These results pro-vided a major stimulus for the application ofimmunotherapy with Campath-1, whichdepletes dendritic cells and monocytes aswell as T cells, as a component of stem celltherapy in recipients6,7. In addition, becausehost dendritic cells in the liver, spleen andmost lymph nodes are rapidly replaced bydonor stem cell–derived precursors4, thesefindings added impetus to approaches thataimed to lessen GVHD by delayed T cellinfusions.
As is often the case, however, clinicalexperience showed that things may not beso simple. Patients receiving delayed T cellinfusions were not fully protected fromGVHD, and in particular, they appearedsusceptible to chronic GVHD, often withintense skin involvement8. Either not allhost dendritic cells were replaced by donor-derived dendritic cells, or donor dendriticcells themselves were able to trigger GVHD.Amidst this conflicting maelstrom of labo-ratory and clinical data, a surprising clueemerged from Merad et al.9, who found that
Stephen G Emerson is in the Department of
Medicine and the Abramson Cancer Center,
University of Pennsylvania School of Medicine,
Maloney 510, 3600 Spruce Street, Philadelphia,
Pennsylvania 19104, USA.
e-mail: [email protected]
Tanning before transplant: lancing the Langerhans cellStephen G Emerson
Ultraviolet radiation thwarts graft-versus-host disease in mice after hematopoietic stem cell transplantation. Thetreatment kills host Langerhans cells in the skin, which contribute to this deadly disease (pages 510–517).
NATURE MEDICINE VOLUME 10 | NUMBER 5 | MAY 2004 451
XRT (Bone marrow depletion)
T cell depleted bone marrow
Epidermis
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TNFα
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Donor T cell
Donor T cell
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+ UV radiation
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Donor dendritic cell
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a
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Fas/FasL
Figure 1 Catching some rays. (a) Normal tissue. (b) Bone marrow stem cell transplantion withhematopoietic cells fully depleted of T lymphocytes results in bone marrow stem cellreconstitution. All dendritic cells and macrophages in lymph nodes and spleen are replaced bydonor-derived cells, but Merad et al. show that Langerhans cells in the skin of these mice remainhost-derived. (c) Direct infusion of donor T cells and bone marrow stem cells into these micecauses severe donor T cell anti-skin reactions (cutaneous GVHD). (d) Treatment of these mice withUV light prior to transplantation with donor T cells plus bone marrow stem cells preventscutaneous GVHD.
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N E W S A N D V I E W S
Langerhans cells renew locally throughoutlife without reconstitution from bone mar-row precursors.
If Langerhans cells remain of host originafter transplantation, then they would pro-vide a constant reservoir for host antigenpresentation, likely contributing to ongoingcutaneous acute and chronic GVHD.Moreover, Langerhans cells in the skin seemto—somehow—generate dendritic cells inlocal draining lymph nodes, theoreticallyproviding a trigger for more generalizedGVHD reactions.
In the new study3, Merad et al. show thatskin Langerhans cells indeed remain host-derived following transplantation––unlessdonor T cells are included along with donorstem cells. Inclusion of donor T cells causesreplacement of host by donor-derivedLangerhans cells through a two-step process.In the first step, donor T cells directly killhost Langerhans cells, predominantlythrough a Fas-Fasl apoptotic pathway. In thesecond step, the inflammatory reaction trig-gered in the skin by donor T cells initiateschemokine secretion and presumably estab-lishes a local chemokine gradient into theskin; this gradient serves to chemo-attractdonor hematopoietic Langerhans cell precursors.
Thus, recipients of typical T cell-con-taminated transplants, unlike those of fullyT cell-depleted transplants, eventually haveonly donor-derived Langerhans cells intheir skin. Unfortunately, including T cellsin the donor graft causes GVHD beforeLangerhans cell turnover can occur. As aconsequence, Langerhans cell chimerism(replacement with transplant-derivedcells) doesn’t necessarily provide GVHDprotection.
But all is not lost. Armed with the knowl-edge that skin repopulated with donorLangerhans cells will not trigger GVHD,Merad et al. now suggest a sequential strat-egy to fool the host immune system, basedon their experiments in mice. First, theyuse fully T cell-depleted hematopoieticstem cell transplants to populate the hostwith donor stem cells. This approachshould repopulate APC compartmentsexcept the skin, and perhaps other similarlyprivileged sites.
Next, these primary recipients receive UVirradiation, which ablates Langerhans cellsin the skin, and allows donor-derivedhematopoietic cells to repopulate the skin.APCs are susceptible to UV irradiation, forunclear reasons, and in mice this treatmentkilled Langerhans cells but the skin appearedto be unharmed.
In the last step, Merad et al. proposeretransplanting with hematopoietic stemcells, plus T cells, several weeks later. Underthese conditions, with the skin Langerhanscells nearly fully replaced by donor-derivedcells, the mice did not develop GVHD. Thus,if one could rapidly encourage cutaneousLangerhans cell chimerism in patientsundergoing transplantation prior to T cellinfusion, they should be protected from sub-sequent skin GVHD.
This hypothesis should be directly testablein the clinic. UV could be incorporated intopre-transplant recipient preparative regi-mens (particularly those that usechemotherapy only and do not include X-irradiation for stem cell ablation). In theMerad et al. study, however, mice weretreated with UV irradiation months after aninitial transplantation—after donor recon-stitution of non-skin hematopoietic com-partments. It is therefore possible thatsimultaneous UV irradiation and T-cell con-taining transplants in the clinic may not
allow sufficient time for donor Langerhanscell reconstitution and prevention of donorT cell homing to the skin.
A two-step approach may be needed, analo-gous to the mouse experiments of Merad et al.,in which UV treatment occurs before delayedT cell infusions. In any event, these mousemodel studies suggest that targeted UV thera-peutics to prevent cutaneous acute and chronicGVHD is an ideal candidate for careful andsystemic translation to the clinic. HostLangerhans cells should not be left to languish.
1. Shlomchik, W.D. et al. Science 285, 412–415(1999).
2. Ruggeri, L. et al. Science 295, 2097–2100(2002).
3. Merad, M. et al. Nat. Med. 10, 510–517 (2004).4. Zhang, Y. et al. J. Immunol. 169, 7111–7118
(2002).5. Teshima, T. et al. Nat. Med. 8, 575–581 (2002).6. Ratzinger, G., Reagan, J.L., Heller, G., Busam, K.J.
& Young, J.W. Blood 101, 1422–1429 (2003).7. D’Sa, S. et al. Br. J. Haematol. 123, 309–322
(2002).8. Marks, D.I. et al. Blood 100, 3108–3114 (2002).9. Merad, M. et al. Nat. Immunol. 3, 1135–1141
(2002).
452 VOLUME 10 | NUMBER 5 | MAY 2004 NATURE MEDICINE
Finally, mice with CF lung diseaseRaymond A Frizzell & Joseph M Pilewski
Increasing sodium absorption by overexpressing the epithelial sodiumchannel in mouse airways results in mucus accumulation and inflammation,changes that occur in the lungs of individuals with cystic fibrosis. Thedevelopment of lung disease in these mice should provide insights into adisease that has long been lacking an animal model (pages 487–493).
Despite advances over the last few decades,patients with cystic fibrosis typically die ofobstructive lung disease by their mid-30s.Following discovery of the responsible genein 1989, the work of many scientists impli-cated the cystic fibrosis transmembrane conductance regulator (CFTR) as a cAMP-stimulated anion channel that was missingfrom the apical (lumen-facing) membranesof cystic fibrosis airway cells1. The inser-tional knockout of the corresponding genein mice promised to provide a long-awaitedanimal model for cystic fibrosis, to better
define the role of defective CFTR in lung disease. However, CFTR null mice did notlive up to their promise, as they failed todevelop lung pathology that mimics thehuman disease2.
Years after creation of CFTR knockout mice,researchers have finally created a mouse withlung pathology similar to human cystic fibro-sis. Rather than disturbing the function ofCFTR, Mall et al.3 generated mice that absorbexcess sodium in their airways, as reported inthis issue. These animals show key abnormali-ties of cystic fibrosis, including airway obstruc-tion with dehydrated mucus, and they havealready begun to yield answers to some impor-tant questions about the development of lungpathology, such as the origin of the inflamma-tion that leads to lung destruction. In thefuture, these animals should be useful for eval-uating at least some therapeutic interventionsto treat cystic fibrosis lung disease.
Raymond A. Frizzell and Joseph M. Pilewski are in
the Departments of Cell Biology and Physiology and
of Medicine, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania 15261, USA.
e-mail: [email protected] or
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