Toll like receptors in Chronic Lymphocytic Leukaemia

HSCT literature review

fJ

fJ The rolle of complement system In Haematopoletic stem cell transplantation (HSCT)

exploring current therapies and new developments.

Abstrw:

Being autologous (the paf t's own stem cells are used) or allogeneic (the stem cells come from a donor), Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It is commonly used to treat haematollogical, and increas.ingly, non-hae logical disorders (NHS Commissioning board, 2013). Following the first donor recruitment drive in 1973, the number of bone marrow and peripheral haematopoietic stem cell donors has increased all over the wor,ld with more than 18 million donors now regist.ered (Gluckman, IE, 2015).

fJ Literature Review:

Hematopoietic stem-cell transplantation is used priw for hematologic and lymphoid cancers but also for many other disorders. Donors receive granulocyte­ colony stimulating factor (G-CSF) to mobilize haemato oietic stem cells (HSCs), which are collected by leukaQheresis (where abnormal white blood cellls are separated fro'fl sample of blood) (Cancer Research UK. 2015). In autolog!ous HSCT there's a reduced risk of infection during the immune-compromised stag:e of the tre ent as the recovery of the patient's immunity is rapid. In allogeneic HSCT, as the patient is given donor stem cells, this may cause an immunological response. The donor is likely to be a close relative such as a sibling, with a close match for the human leucocyte antigen (HLA). However, the risk of leukaemia rellapse and mortality with autologous HSCT is higher than for allogeneic HSCT.

OOn0,11'

(H matthed sibl ng or unrela ed donor)

( )

Pon m_rrow a pirated froirn

(b)

1

Hclflt,n,nd & p ......

Figure a: Allogeniic SCT and b: autologous SCT

P;i t

(re pi nt)

Pt nt

Patients are prepared for HSCT by a conditioning regimen involving chemotherapy al radiation, which can be myeloablative or non-myeloablative.

• M eloaola tive regimens- These re desi nea to kill all resiaual cancer cells in auto-ous o� allogenic transplantatio .

• No n-m eloablative re imens - These a re immunosu Qressive and rell on the raft­ il/ersus-tumour effect to kill tumour cells with donor T cells and is typically used in high-risk patients.

A complicatio n in this is graft versus host diseas e (GVHD). GVHD happens when articular ty__Qes of white blood cell (T cells in the donated bone marrow or stem cells

attack our own bod cells. This happens because thlj>nated cells (the graft) see �our bod cells (the host} as forei n and a ck the . Acute GvHD (aGVHD) occurs

.

ost freguentl after engraftment, leading to an arbitrary period of 100 days post HSCT which has defined the acute versus chronic manifestation ofthi1s disease. The characteristic pathologic feature of aGVHD is target tissue (skin, liiver, gastrointestinal [GI] tract) apoptosis. aGVHD was initially described as a "cytokine storm" involviing a three�step disease process. These steps involve:

1) transplant conditioning and associated inflammation:

Foll owing conditioning (radiation and/or chemotherapy), the integrity of the GI mucosa becomes compromised allowing the release of DAMPS and PAMPS. These in turn promote the production of pro-:inflammatory cytokines from recipient cells. These cytokines contribute to host APC (hematopoietic and non-hematopoietic) activation in the gut and lymphoid tissue. GVHD impacts on the gut micro biota, reducing iits diversity with a loss of enteric commensal organisms and an outgrowth of pathogenic microbes that further aggravates the pathological DAMP/PAMP ca scade.

a

CONDITIONING TISSUE DAMAGE

I ,

RADJATtON

I

I

I \ ( \

\

•

CHEMOTHERAPY

t MHC Ci>itimuladon

Figure 1: GVHD pathophysiology phase 1- transplant conditloning1 and Inflammation.

a 2) Donor T-cell priming and differentiation:

Donor CD4 T cells contained within the graft are activated by the inflammatory

environment early after conditioning, facilitating their rapid access to the gut and

lymphoid tissue. Once in the gut, MHC class II-expressing recipient non­

hematopo1ietic APCs ca n initiate priming to host antigens while recipient

hematopo,ietic APC initiate priming In lymphoid tissue. Recipient hematopoi:etic APCs

appea.r to be the dominant APCs for CD8 T-cell priming. Donor APCs can further

ntribute to this priming process. Activation in the presence of various cytokines

instructs T-oell differentiation along specific lineage pathways (type 2:, type 117, and

type 1 , respectively). The tra.nscription factors GA T A-3, RO Rgt, and T-bet are critica I

for these Th2, Th17, and Th1 differentiation pathways. Tregs are differentiated in the

presence of I L-2 and TGFb (in the absence of IL-6) and abrogate the differentiation

of effector T cells via effects on DCs and effector T cells themselves.

•

lymph

node

-

ll-12

IL�

TGFP

Figure 2: Phase 2- donor T-cell priming and differentiation.

GAlA•3

3) An effector phase of tissue apoptosis mediated by inflammatory

cytokines and cellular (T and NK cell) effectors:

• • During the effector phase of GVHD, inflammatory cytokines derived from

macrophages and T cells mediate apoptosis in target tissues, particularly within the

gut. Donor Th 1 /T c1 , Th2/T c2, and Th 17 /T c17 cells e I icit GVH D wi1th relatively tissue­

specific patterns mediated in part by their respective chemokine profil'es and the

relative sensitivity of the target to effector cytokines generated by each lineage.

Cytolytic T and NK cells mediate antigen-dependent killing of targetti issues via the

perforin/granzyme and TN F member pathways.

SKIN

LUNG

LVER

TNF/LTa

IL-6

Figure 3: GVHD pathophysiology phase 3- the effector phase.

Meticulous supportive care is vital for P-atients with both acute and chronic GVHD

owing to the extended duration of immunosu9-pressive regimens as the man drugs

administered could have synergistic toxic effects. Such care includes early

interventions in cases of suspected infections, extensive infectious prophylaxis, and

prophylaxis against non-infectious side-effects of drugs 1table). These complications

need rapid responses to prevent serious, irreversible damage and are best handled

by a close and efficient colllaboration between the primary doctor and th,e transplant

specialist.

Table 1: Recommendations for supportive care

Other

Viral lnfec:dons

Cyt.:ome:ga1avirus

�sprrato,y viruses

fi!v«, chil s, pain,

erythema

Fewr. (hills,; sepsis

symptoms

Gastroenteritis.

Routln�·mQnltQring

Clinical�. che,t radiCJ!iraph

or CT scan for pos,lble

pneumo.,:ie

Blood cytomeg.aknrirus PCR Ol

lntemltli!I p,,eurr,onla pp6S ant gen l'l!"els

Symptoms of uwer or Cllnle<1I monitoring

low1:r ,,�r,torr-tract

in·fe,etiom

Varictll'a•tost« virus 1/ciielilar skin I sions Clini�I monit,0�114

Funpl and othet Infections

Asperglllo,1$, other

�m .....,.fungal

infections

candida

l'neumocy,tis

Jl\llmona,y lesions, Galaetom�nnan, usavs In

sinusitils. stin nodules high-risk pa�cnts. CT $G;lO if

signs of infectio n

Th,ust,, pvlmonarr

k!sioru

Fe\lef, hypo - ii;

resplratorydl,tress

Clinical eomim:ation,. CT scan if

signs: of infection

Clintcal a ssessment

Otflertoxic effects of Im munosuppres.sive :agents

Cllcineurininhibitors. Tremor Clintcal .asses.s:me11t.. ,drug

t;Qn(entrat1Qfl$

Caldneurlnlnhll>ltors N·eurotaxk effects Assess mental slat.us

Calcineurininhibitor5- Renalimp.airment Creatini.ne· le..-ets. ilnd gk,merular

flltr.atloo r.at,e,

Caldneurlnlnhll>ltor$ Hypertensfon Blood pressure monitoring

�lclneurloinhlbltor$, Trans?1uN1ssoci.t d /Weubloodsm arfor

Cortirnsteroids

Curlirosieroids

Corllrosterolds

Lat.i eraft 111ilur.

81ood disorder$

microonsiopathy

Oislla,(s dise.1st

symptoms

Diabetes

l!leedlnB wrnpto�

aMemi:I

Tllitk, R-mmendalions for SltPPor1 i...e �re

ha.emolysis, sch�tocytes

Assessment of llooe density

Sloodc()<)nt,

AntibiOti(;.$ in hi(h•ililk �tientS (hill,IH!OSt

torticosterolds o.r .aspfenia). lntravenaus.

lmmunoglobu11n If lgG, level <AO() g/l

Pfe-emptlYe treatment in ,p.atient:s with reactivation

Annual lnftuenzo vaccination (stardns 6 month$ post

Hcr), •a,«ln.ition of eares,\>ers

Aciclovir prophylaxii

Vorloonazole, or pol.(!Conatole proph'(la•ls In hlgh-rl�k

patients l�g. high·d0<1e steroids)

�lucon.nole jaspergillus prophyl•�is prote<:ts �ga inst

c.rndida too)

CotrilillO.Xarole. or pentamadine until 1 rrnonth off

mmunosuppre.u1on

Adjust dose todesired trough levels

Adequate fluiduptate(about 3 l pe,darl

utrition:al gvida nee

Obc,in cgtEutM, �mmtdi�t·� intravt'ftOus

.antibfotic treatmenl. ,,emove line

Obtain tuitvtt$:, imrnediat� inttavenous

broad-sp,,ctrum antibiotics, became of'risk of

oveMhelmlngsepslswithln ho 1s

Antiviral treatment lg.anclclovir. v.alganciclovir.

orfoscarnet)

E'.arlv t,eatment with neuramlnld�se fnhlb!to,s

(lnftuenu), other antislral$

Trcatmnnt dom of anti,irals

Anti fungal trealment

T reatme:nt d05es of'.a nti•PCP drugs

,Stop caldneurln Inhibitors

lntravenoo:s. fluids

Anti hypertensive treatment

(angiorer\sln,.ecn.e,rtln-lt'enzvme l!\hlblto,,,

�-blockil'\8 agents),

Stop ca clneurin lnt.lbl1ors, plasrnapher.uls

Insulin tre:atment

Growth, "1c1or� [&raouloevte eclonv-$\lmul;illns

'foetor), �roJlO('ti"1, ttMrlu!iOns

As touched upon earlier, an increasingly frequent treatment for GVHD is

extracorporeal photopheresis. During this, the patient's white blood cells are gathered

by apheresis, incubated with the DNA-intercalating agent 8- methoxypsoralen,

exposed to ultraviolet light, and returned to the patient. Extra.corporeal photopheresis

is known to indte cellular apoptosis, which has strong anti-inflammatory effects in

several syste s, including prevention of rejection of solid organ gra. fts. Experiments

conducted on animals shows that extraco, rporeal photopheresis reverses acute

GVHD by increasing the number of regulatory T cells in blood {Ferrara,J et al. 2009).

The number of allogeneic haemo12oietic-cell transplantations (HCTsJ continues to

rise, with over 25 000 procedures undertaken annually. The graft-versus-leukaemia

or graft-versus-tumour effect during this Qrocedure effectively eradicates many

haematollo ical malignant diseases.

Over the last 60 y,ears, animal models have played a crucial role in shaping the

understanding of GVHD and GVL responses. This could possibly be the greatest

contribution to the field. Nonetheless, they have also generated major new

paradigms that have instructed clinical practices. As we move forward, it is useful to

consider where the next advances will come from and how we should assess the

potential of a therapeutic intervention defined in a preclinical study to translate into

clinical practice (Markey,K et al. 2014).

While randomized trials provide some way to directly compare transplantation

strategies over a set of pre-defined endpoints, these studies are challenging to

conduct because of time involved and the cost as well as the difficulty of generating

adequate sample sizes wi�hin single-centre or oligo-centre studies. Randomized

studies in HSCT r,equire a llarge amount of planning and large cooperative

infrastructures, which cannot easily keep up with the rapid development of new

HSCT strategies. Many of the changes in HSCT practice are therefore likely to come

from the interpretation of non-randomized studies.

l

International collaboration through a number of non-profit organisations has been a

key factor for �he development of haematopoietic stem celll transplantation.

Thanks to the dedication and far-sighted view of a few pioneers, it was realised that

it is essential to work together in order to facilitate the development of

haematopoietic stem cell transplant, help new centres and laboratory facilities to be

established, provide guidel ines, develop accreditation through JACIE and promote

the development of new research protocols.

Refer,ences:

Canoer Research UK. (2015). What is leukapheresis?. Available: http ://www. cancerresearchu k. org/a bout-cancer/cancers-in-general/cancer­ questions/what-is-leu ka pheresis. Last accessed 9th January 2015.

Ferrara,J, Levine.,J, Reddy,P, Holler.IE, .. (2009). Graft-versus-host disease. Seminar.

373 (3), p1550-1557.

Gluckman, IE. (2012). A brief history of HSCT . In: Gluckman, IE The, EBMT

Handbook 2012 edition. London: . p22-25.

Markey,K, MacDonald,K, IHillll,G. (2014). The biology of graft-versus-host disease:

experimental systems instructing clinical practice. http://www. bloodjournal. orgkontent/124/3/354. full.html. 12:4 (3), p354-359.

NHS Commissloning Board. (2013). Clinical Commissioning Policy: Haematopoietic

Stem Cell Transplantation (HSCT) (All Ages).Available:

https://www.engiand.nhs.uk/wp-content/uploads/2013/1 O/b04-p-a.pdf. Last accessed

26th December 2015.

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HSCT literature review ORIGINALITY REPORT

PRIMARY SOURCES

www.ncbi.nlm.nih.gov Int ernet Source

Submitted to University of Westminster St udent Paper

Ferrara, J.L.. "Graf t-versus-host disease", The Lancet, 20090502/08 Publicat ion

www.eurocord-ed.org Int ernet Source

gastroindia.net Int ernet Source

en.wikipedia.org Int ernet Source

www.cancerresearchuk.org Int ernet Source

emedicine.medscape.com Int ernet Source

www.nature.com Int ernet Source

Warren D. Shlomchik. "Graf t-versus-host

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disease", Nature Reviews Immunology, 05/2007 Publicat ion

R M Egeler. "Acute GvHD: pathogenesis and classif ication", Bone Marrow Transplantation, 06/2008 Publicat ion