Helthline VOLUME 9 Corm * Continuing Eduction Progrm Overview of the Immune System in Trnsplnttion The immune system is complex, interctive nd essentil for survivl. In trnsplnt, however, some of the ody s norml immune responses re counter-productive. Without modulting the norml immune response, trnsplnttion could not e successful. This self-study continuing eduction progrm will review the foundtion of immunity nd the immune process to support understnding of the role of the immune system in trnsplnt, including immunomodultion to crete n environment with less risk of rejection. Of the five primry roles of the immune system (see ox), protection nd tolernce re the most relevnt to trnsplnttion. Protection is essentil in order to prevent infection. And tolernce would cuse rejection in the solid orgn trnsplnt, or grft-versushost disese (GVHD) in the stem cell trnsplnt. Purposeful wekening of tht response is necessry for successful trnsplnttion; however, tht sme wekening plces ptients t greter risk of infection. In solid orgn trnsplnt, it is the trnsplnt recipient s immune system tht recognizes the donor The Primry Roles of the Immune System orgn (the grft) s foreign or non-self nd ttempts to reject it. In one mrrow or lood cell trnsplnt, the trnsplnt is not of n orgn ut of new one mrrow nd new hemtologic nd immune system. Thus, when cells from this grft develop nd re relesed, they see the rest of the ody tissues s foreign nd try to reject them. Innte nd Adptive Immunity Innte immunity refers to nturl, non-specific inflmmtory response, such s the influx of T-cells t the presence of pthogen, or the engulfing of pthogen y phgocyte. Adptive immunity refers to n cquired, specific lerned response, such s the development of ntiodies. Both types of responses rect to ntigens. Antigens re the foreign cells tht enter the ody. The immune system must e le to recognize nd tolerte the ody s own cells. Every cell in the ody crries distinctive molecules or mrkers; it is the unique mrkers tht identify cell s self. A molecule tht is recognized s nonself for exmple cteri, pollen yprotection: Defend ginst pthogens ysurveillnce: Recognize nd destroy norml cells yhomeostsis: Remove dmged cells ytolernce: Differentite self from non-self yregultion: Turn the immune response on/off s pproprite for some people, nd humn tissue (s with orgn nd one mrrow trnsplnttion) is n ntigen. The greter the difference etween the ntigens nd the self cells, the stronger the immune response. Antiodies re formed ginst specific non-self ntigen. For exmple, n ntiody ginst one strin of cold virus would e ineffective ginst different strin. Antiodies ttck the ntigen in order to destroy it, nd upon reexposure to tht ntigen, rpidly ttck it to prevent re-infection. The innte immune system is lso referred to s cellulr immunity. As mentioned, T-cells re the first to respond to the presence of nything non-self. Cellulr immunity is prticulrly ctive ginst viruses, for exmple. The T-cells trnsfer their knowledge to B-cells for specific ntiody production. This humorl immunity plys mjor role ginst cteril pthogens. The cells, tissues nd orgns tht re responsile for the immune response re found in the lymphoid system, primrily in the thymus (thymocytes) nd one mrrow, ut lso in other sites throughout the ody. Hemtopoiesis is the formtion nd development of ll of our lood cells from unique prent cells clled stem cells. Stem cells re primitive, undifferentited lood cells. They hve yet to declre themselves s, for exmple, T- or B-cells, red cells, white cells, or pltelets. For tht reson, stem cells re often referred cormhc.com/ce CEDept@cormhc.com *Corm CVS Specilty Infusion Services
to s pluripotent they differentite into myeloid or lymphoid lineges (see Fig. A elow). Stem cells give rise to progenitor cells, which grdully develop into specific functioning cells. As mentioned ove, the stem cell differentites into two lineges, myeloid (eventul white cells) or lymphoid (eventul B-cells nd plsm cells). Ech step represents key components of the hemtopoietic process nd requires, for exmple, colony stimulting fctors (CSFs) nd interleukins (ILs). On the lymphoid side, the one mrrow is the site of initil lymphocyte formtion. However, the mjority of circulting lymphoid cells, oth T nd B, re produced in the peripherl lymphoid tissue (lymph nodes, spleen, thymus nd lymphoid tissues of the gstrointestinl nd respirtory trcts). Lymphocytes mke up less thn 10% of the norml one mrrow mlgm. The cells in the group of white lood cells (neutrophils, eosinophils nd sophils) re primrily phgocytes. Along with lymphocytes, ntiodies nd complement, they function s the mjor defense ginst microorgnisms. The monocytes re immturelooking cells tht spend only short time in the mrrow. They circulte in the lood for 20 to 40 hours until they move into tissue, where they my survive for severl months or even yers. The mcrophge either removes the ntigens or presents them to lymphocytes. The phgocytic cells form network known s the reticuloendothelil system (RES) nd re found in the orgns, such s in Kupffer cells in the liver, in lveolr mcrophges in the lungs, nd in mesngil cells in the kidneys. Mture T-cells mke up out 65 80% of the circulting lymphocyte popultion. The cell surfce contins ntigen receptors. T-cells mture in the thymus nd migrte etween lood nd lymph fluid. They hve two mjor functions: 1. Regultion, such s iding B-cell function, ugmenting cytotoxic T-cell ction nd, when needed, suppressing ntiody nd T-cell effect or function. 2. Initition of delyed hypersensitivity rections, lysis of ntigens, nd production of lymphokines. Nturl killer cells re smll popultion of lymphocytic cells tht re le to kill tumor cells nd cells virlly infected. They re lso involved in grft rejection. Cytokines re produced primrily y the T-cells, ut lso y monocytes nd mcrophges. Cytokines include interleukins, lymphokines, interferons, tumor necrosis fctor, nd others. They ind to plsm memrne receptors nd ffect the growth nd differentition of white lood cells. Cytokines re the key to regultion of the immune system. They often work together to either potentite or inhiit the immune response, depending on wht is needed. B-cell lymphocytes comprise 5 15% of the circulting lymphocytes. Mture B-cells re defined y the presence of immunogloulin molecules, which Fig A. Cells of the Immune System Stem Cell Lymphoid Stem Cell Myeloid Progenitor Lymph ocytes Grnul ocytes B Cell Progenitor T Cell Progenitor Nturl Killer Cell Neutrophil Eosinophil Bsophil Mst Cell Monocyte Th Cell Tc Cell Memory Cell Dendritic Cell Plsm Cell Mcrophge www.textookofcteriology.net/dptive_2.html 2 Corm Continuing Eduction Progrm
re produced endogenously (in the ody). These molecules re on the cell s surfce memrne, where they ct s receptors for specific ntigens. Histocomptiility in Trnsplnt The HLA (humn leukocyte ntigen) system, the mjor histocomptiility complex (MHC) in humns, is controlled y genes locted on section of the sixth chromosome. Histocomptiility refers to the tolernce or comptiility of humn tissue to humn tissue. The MHC consists of HLAs. The more like the HLA of the donor nd recipient, the less the immune system s effort to reject. This degree of comptiility is n importnt fctor in trnsplnt. Tissue typing is the nme given to the test tht identifies n individul s HLA nd mtches the donor tissue with the recipient y compring HLA type. There re mny different HLA ntigens, ut the ones now known to e most importnt for trnsplnttion re HLA-A, HLA-B, nd HLA-DR. HLA ntigens re polymorphic, mening their form is different in different individuls. Thus, within popultion they cn e found in mny different forms. There re more thn 25 forms of HLA-A, more thn 50 forms of HLA-B, nd more thn 15 forms of HLA-DR. Refer to Fig. B on pge 4. Imgine tht the second oldest child is the potentil trnsplnt recipient. Within fmily, ech child should e hlf-mtch, or 3/6 mtch, with ech prent. There is 25% chnce tht two silings will e perfect 6/6 mtches, 25% chnce tht they will shre no HLA ntigens, nd 50% chnce tht they will e hlf-mtch. Often, however, there re no fmily memers to consider s donors. In the cse of solid orgn trnsplnt, mny ptients hve to look to n unrelted donor (either decesed or living). Mny lood cell trnsplnt (BCT) ptients hve to look outside the fmily s well, given tht mtching is prticulrly importnt in BCT. As there re thousnds of potentil HLA comintions, it is extremely difficult to find donor with ny mtch to recipient. Tht is why the donor mrrow registry exists to ssess lrge pool of potentil donors. When cdver orgns re donted, the donor HLA is otined nd compred to tht of the people witing for tht orgn on the witing list. Mtching is often prt of the determinnt for orgn distriution. Rememer, the greter the mtch, the less immune response is expected. Ptients cn lso hve ntiodies ginst HLA ntigens s prt of prior exposure nd the lerned response. Ptients my e exposed to humn tissue ntigens in severl wys: y Through pregnncy. The pregnnt womn is exposed to the fther s ntigens through the fetus. y Through lood trnsfusions. A ptient is exposed to ll the lood donors from whom they hve ever received lood. y Through trnsplnt. A previous trnsplnt exposes ptients to tht donor s six HLA ntigens. Some ptients uild ntiodies ginst these ntigens. They re sensitized this mens they hve ntiodies ginst humn tissue nd rect ginst mny potentil donors. Some ptients will only rect towrd few HLA ntigens; some will rect to mny. A trnsplnt using donor to whom the recipient hs ntiodies would result in rpid nd irreversile rejection. How mny nd even which specific HLA ntiodies ptient hs in their lood cn e determined with lood test, thus llowing the trnsplnt tem to void those ntigens when selecting n pproprite donor for specific recipient. If the ptient does not hve HLA ntiody to possile donor, the test result will e negtive. The ntiody screening procedure lso identifies how much HLA ntiody the ptient hs. For exmple, if the ptient rects with 30 out of 60 cells, then the ptient is sid to hve 50% ntiody for tht prticulr serum dte. This percent ntiody is clled the PRA (pnel rective ntiody). It is difficult to find donor to which this ptient would not rect. Whether recting ginst one or five ntigens, positive rection dicttes tht the ptient cnnot receive tht donor s orgn. Highly sensitized ptients represent pproximtely 20 30% of trnsplnt witing lists. There is limited chnce for trnsplnt for this ptient popultion. At minimum, highly sensitized ptients hve wit time (time on the cdver trnsplnt witing list) of severl yers. If trnsplnted, sensitized ptients re more likely to experience n incresed numer of rejection episodes nd, ultimtely, poorer grft survivl. Immunomodultion in the Fce of Sensitiztion Firly recently, protocols for downregultion of the highly sensitized ptient s immune system hve een incorported. Using plsmpheresis nd/or intrvenous immunogloulin (IVIg) nd lymphocyte-reducing gent such s rituxim hs proven to decrese the level of donorspecific ntiodies. Since ntiody levels eventully reound, oosters my e required s the ptient wits trnsplnt opportunity. Volume 9 3
Fig. B 3,14,17 10,16,8 Fther Mother 3,14,17 10,16,8 3,14,17 10,16,8 Brother You* Sister Brother* Sister *Identicl mtch Rejection in Trnsplnt: Solid Orgn Trnsplnt vs. Blood Cell Trnsplnt In solid orgn trnsplnt the ptient is the host nd the new orgn is the grft. The grft is the foreign oject so the host nturlly tries to reject it, i.e. host versus grft. In llogeneic lood cell trnsplnt the grft is the new lood cells (new immune system) nd it is tht grft tht crries the immune cells. In llogeneic trnsplnt it is nother donor supplying the immune system so, s tht new system engrfts nd replictes, nd is sent out into circultion, it is the ptient (the host s) tissues nd cells tht re foreign to the new immune system, i.e. grft versus host. Cross-mtch If the ptient hs ntiodies to the donor HLA, this is referred to s positive crossmtch. A positive crossmtch signifies tht the ptient will rect ginst nd destroy the donor s cells, injuring the donted orgn. Therefore, positive crossmtch is contrindiction to trnsplnt with tht donor. A negtive crossmtch indictes tht the ptient does not hve the HLA ntiody ginst tht prticulr donor, nd trnsplnt cn e performed. Rejection As descried, it is nturl function of the immune system to reject something foreign, s the system does not differentite etween eneficil foreign oject (the trnsplnt) or hrmful one. Rejection is common occurrence in oth orgn nd lood cell trnsplnt. Immunomodultion continues post-trnsplnt, with the use of immunosuppressive medictions, in order to weken the rejection response. The gol of immunosuppression is to weken the immune system in order to prevent rejection or GVHD. The consequence is wekened immune system. It s doule edged-sword, nd getting the right lnce for ech individul ptient is chllenging. Too much nd the ptient is t risk for infection; too little nd the risk is for rejection or GVHD. t References 1. Vo, AA, Peng, A, Toyod, M et l. Use of intrvenous immune gloulin nd rituxim for desensitiztion of highly HLA-sensitized ptients witing trnsplnttion. Trnsplnttion. My 15, 2010;89(9):1095-1102. Do not use the informtion in this rticle to dignose or tret helth prolem or disese without consulting qulified physicin. Ptients should consult their physicin efore strting ny course of tretment or supplementtion, prticulrly if they re currently under medicl cre, nd should never disregrd medicl dvice or dely in seeking it ecuse of something set forth in this puliction. 4 Corm Continuing Eduction Progrm
Self-Assessment Quiz: Overview of the Immune System in Trnsplnttion LEARNING GOAL To understnd the complexities of the immune system nd the implictions for solid orgn nd lood cell trnsplnt. LEARNING OBJECTIVES Upon completion of this continuing eduction progrm, the reder will e le to: 1. Descrie the concepts of self nd non-self. 2. Differentite etween innte nd dptive immunity. 3. Descrie the role of the stem cell. 4. Identify the primry roles of T nd B lymphocytes. 5. Define the mjor histo-comptiility system nd HLA ntigens. SELF-ASSESSMENT QUESTIONS In the Quiz Answers section on the next pge, fill in the correct nswer for ech question. To otin two (2.0) contct hours towrd CE credit, the pssing score is 100%. Return your Self-Assesment Quiz to Corm vi emil or fx. See the next pge for detils on how to return to your quiz. Plese llow pproximtely seven dys to process your test nd receive your certificte upon chieving pssing score. 1. Tolernce is the ility of the ody to differentite etween self nd non-self.. True. Flse 2. Non-self refers to nything tht is foreign to the immune system.. True. Flse 3. In lood cell trnsplnt, non-self is the ptient s own tissue/cells.. True. Flse 4. Innte immunity is:. Non-specific.. The nturl response of the ody to foreign ntigen. c. The erly response of the immune system to foreign ntigen. d. All of the ove. e. A nd B. 5. Adptive immunity:. Centers round non-specific ntiody formtion.. Centers round specific ntiody formtion. c. Provides lifelong immunity. d. A nd C. e. B nd C. f. C. 6. B-cells re the first to respond in the presence of n ntigen.. True. Flse 7. T-cells ct to kill invding pthogens.. True. Flse 8. The stem cell:. Is pre-determined s to which type of cell it will eventully develop into.. Divides into myeloid cell lines nd lymphoid cell lines. c. A nd B. 9. Tissue typing is the nme given to the test tht identifies n individul s HLA nd mtches the donor tissue with the recipient y compring HLA type.. True. Flse 10. A positive crossmtch indictes HLA incomptiility etween recipient nd donor.. True. Flse Volume 9 5
Helthline VOLUME 9 Corm * Continuing Eduction Progrm Overview of the Immune System in Trnsplnttion QUIZ ANSWERS Fill in the key elow with the correct nswers to receive 2.0 Continuing Eduction credits.** 1. 2. 3. 4. 5. 6. 7. 8. 9. c d e c d e c 10. **Accredittion Informtion Provider pproved y the Cliforni Bord of Registered Nursing, Provider Numer 15200 for 2.0 contct hours. Corm CVS Specilty Infusion Services is pproved y the Delwre Bord of Nursing, Provider Numer DE-14-010517. Corm CVS Specilty Infusion Services is pproved y The Commission for Cse Mnger Certifiction to provide continuing eduction credit to CCM ord certified cse mngers. Corm CVS Specilty Infusion Services is Continuing Professionl Eduction (CPE) ccredited provider with the Commission on Dietetic Registrtion (CDR). Registered Dietitins (RDs) nd Dietetic Technicins Registered (DTRs) will receive 2.0 continuing professionl eduction units (CPEU) for completion of this progrm/mteril. CDR Provider CO100. Provider pproved y the Ntionl Assocition of Socil Workers (Approvl Numer 886613245). Corm CVS Specilty Infusion Services is n pproved provider for the Americn Bord for Trnsplnt Certifiction (ABTC). Corm CVS Specilty Infusion Services will grnt one Continuing Eduction Point for Trnsplnt Certifiction (CEPTC) for this offering. Provider Numer 147. Corm CVS Specilty Infusion Services is ccredited y the Accredittion Council for Phrmcy Eduction s provider of continuing phrmcy eduction. f To otin Continuing Eduction credits, plese complete this informtion in full. Plese print clerly. Nme: Address: City: Stte: ZIP: License Numer (required to receive CEs): RN LPN Certified Cse Mnger Socil Worker Employer: Work Phone: Corm Representtive: Dte: Ws this mteril: Useful in your prctice? Yes No Comprehensive enough? Yes No Well orgnized? Yes No Certificte delivery: I would like my certificte miled to the ddress provided ove. I would like my certificte emiled to me t: (ex: john.smith@cormhc.com) Fx this pge to Corm t 949-462-8990, or SUBMIT FORM VIA EMAIL: CEDept@cormhc.com *Corm CVS Specilty Infusion Services 2017 Corm CVS Specilty Infusion Services. All rights reserved. COR16034-1215 cormhc.com/ce CEDept@cormhc.com