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2-5-10 HCT for Immunodeficiency and autoimmune disorders Autoimmune disorders can be either systemic (systemic sclerosis, systemic lupus

erythematosus, rheumatoid arthritis or or!an specific (diabetics Type I, autoimmune thyroid " Autoimmunity occurs due to# ● $usceptibility, as determined by H%A and other mutations&polymorphisms ○ 'ost autoimmune diseases ha(e a poly!enic !enetic profile ○ In addition to H%A, there are ■ I%2)A and I%*)A associated +ith multiple sclerosis ■ $TAT, for systemic lupus erythematosis ($%- and rheumatoid arthritis ● Initiation by en(ironmental or internal tri!!ers ● .ro!ression (ia increase in tar!et autoanti!ens (epitope spreadin! ● Tissue in/ury, tri!!erin! autoreacti(e T cells and antibodies 0here can +e !et H$C1s2 bone marro+, peripheral blood, and cord blood" They can be sourced from an a donor (allogeneic or from the patient or an identical t+in (syngeneic3 ● 4or patients +ho +ill benefit from an allo!eneic 5' transplant but don1t ha(e an H%Amatched siblin!, the ne6t best option +ould be an unrelated H%A-matched donor, follo+ed by umbilical cord blood and a related donor +ho is less than perfectly matched ● 3autologous 5' transplant specifically refers to usin! the patient1s o+n stem cells to replenish hematopoeitic cell function follo+in! chemo, deri(ed either from 5' or peripheral blood" Autolo!ous transplants are used for# ○ Conditionin!# allo+in! for hi!h dose chemo 7&- radiation that1s conducted for myeloablation or lymphoablation ○ )econstitution of marro+ and immune system usin! har(ested bone marro+ or mobili8ed peripheral blood stem cells ○ )esettin! the immune system by !ettin! rid of autoimmune lymphocytes, then addin! ne+ ones (ia an autolo!ous transplant ■ In autoimmune disease, the thymus fails to !et rid of autoreacti(e T cells ■ The !oal of autolo!ous transplantation in treatin! autoimmunity is to first immunosuppress the patient +ith hi!h-dose chemo conditionin! follo+ed by immune 9resettin!: by !eneratin! a ne+ na;(e T cell repertoire" In the process, !raft (s host disease must be treated for unless the !raft is T cell depleted33" The process is complete +hen you ha(e complete elimination of autoreacti(e clones and correction of the !enetic defect" ● 33in (i(o depletion is accomplished by antithymocyte !lobulin or monoclonal Abs li<e alemtu8umab" -6 (i(o deplection is done cy C=>,7 cell selection" ○ T cell depletion by selectin! for C=>, ○ 'obili8in! .5$C +ith chemo and ?-C$4 -6amples of autoimmune disorders ● Scleroderma (systemic sclerosis)# (ascular dama!e of small (essels +ith (essel loss@ e6tensi(e fibrosis and the spread of autoantibodies to (arious cellular anti!ens" Helper T

cells (and associated cyto<ines are also implicated" This e(entually leads to (isceral or!an dysfunction and failure ● Multiple sclerosis# demyelinatin! autoimmune CA$ disorder characteri8ed by plaBues of inflammation, demyelination, and !liosis" Can be relapsing remitting or primary progressive" %eadin! cause of neurolo!ic disability in youn! adults" This is ACT $D$T-'IC (only affects CA$ , thus it can be treated +ith HCT HCT has hi!h cormorbidities +hen used in systemic disorders li<e scleroderma" There is a ris< of !raft (s host disease and treatment-related mortaility" -6amples of immunodeficiency disorders ● SCID# lethal con!enital disorder characteri8ed by absence of anti!en specific 5 and T cell responses" It1s caused by o(er 15 mutations, includin! adenosine deaminase, )A?, =AA li!ase etc" .resentaiton (aries dependin! on the mutation, but s<eletal, renal, and neurolo!ic defects are most common, especially in A=A deficiency (+hich causes death in lymphoid pro!enitors " ○ HCT can be performed in utero for $CI=, +here T cell depleted parenteral marro+ cells are in/ected into the peritoneal ca(ity three times at 1E, 1*"5, and 1F"5 +ee<s" It is curati(e for $CI=" ○ -arly screenin! prenatally and on ne+borns impro(es sur(i(al" The !oal is to do early HCT before opportunistic infections ta<e o(er" ● Wiskott-Aldrich Syndrome# G-lin<ed disorder due to a mutation in the 0A$protein that1s in(ol(ed in cytos<eletal function" The mutation causes thrombocytopenia, immunodeficiency and ec8ema, and increases the ris< of lymphoma and autoimmune disease" ○ HCT does not cure 0A$" To do an HCT, conditionin! is reBuired (unli<e $CI= " The HCT pro(ides !ood lon!-term sur(i(al I4 the donor is H%A-matched and related" Hnrelated H%A-matched donors only produce E5I fi(e year sur(i(al" Cord blood HCT also has a !ood pro!nosis" ● CID# hetero!enous !roup of diseases characteri8ed by profound but not absolute defects in T and 5 cell function (this is a 9malfunction: of lymphocytes, as opposed to complete loss of function seen in $CI=@ CI= is less se(ere than $CI= " It1s due to T cells respondin! to non-specific stimuli or allo!eneic cells 7 Abs that are either absent or ha(e increased I!? le(els" CI= can be caused by cyto<ine production defests, C=F deficiency, Jap-*0 mutations, bare lymphocyte syndromes, %4A-1 deficiencies, C=,0&,0% deficiency (hyper I!' syndrome , G-%.$, and Tre! abnormalities (I.-G syndrome " ○ IPE syndrome# G-lin<ed enteropathy characteri8ed by massi(e infiltration of T cells into s<in and !ut, plus multiple autoantibodies, caused by mutation if 4CG.>" It has a poor pro!nosis" ○ HCT is curative for CI=" Conditionin! is necessary (li<e 0A$, unli<e $CI= , success not has hi!h as HCT for $CI=" %ater a!e at dia!nosis and chronic infections are issues for CI= treatment" ?eneral points of usin! HCT to treat immunodeficiency# ● HCT effecti(e for $CI= and CI=, but is dependent on early diagnosis and treatment of chronic infections"