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Bone Marrow Transplants

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Bone Marrow TransplantsConditioningChemotherapy or chemotherapy plus radiationdestroys bone marrow so there is room for newdestroys recipients immune system so it doesn’t destroy transplanted cellsdestroys diseased cells (leukemic or pre-leukemic)These treatments lead to an increased risk for infections during treatmentalso nausea, vomiting, hair loss, skin rash, mouth soresLong term these treatments lead to an increased risk for:sterilityendocrinopathiescancerrarely - vessels in liver swell shut, juandice, liver damagerarely - lung damage or cardiomyopathyFA patients have impaired DNA repair, and thus these treatments areless well tolerated and more risky for themAffected child in this case was treated withcyclophosphamide total body irradiation also needed due to MDS (preleukemia)Introduction of new cellsBone marrow or cord blood is put into the blood of the transplant recipient.The bone marrow cells will travel to their proper locations in the recipient’sbones and establish themselves there.Treatments to prevent infection during immunosuppressionGranulocyte colony stimulating factorto increase white cell productionAnti-fungal (prevent candida and aspergillus)Cefazolin (prevent Streptococcal infection)Acyclovir (prevent herpes infection)Cotrimoxazole (prevent pneumocystis infection)Additional TreatmentsCyclosporin Ato prevent graft versus host (GVH)(the transplanted cells attack the recipient)EngraftmentUsually donor bone marrow cells begin to function in therecipient within 30 days.Affected child in this caseNeutrophils were to target levels by day 17Platelets were to target levels by day 30Blood, 103:1147Long-termAffected child in this caseNo acute or chronic GVH (she had a matched sibling donor)Mild adenovirus gastroenteritis resolved by 3 mosNo other opportunistic infections developedMild drug related toxicity developed in the liverAll medications were discontinued by 24 months post transplant.Molly NashMolly still needs treatment for some of her congenital defects (intestinaland spinal abnormalities)Her risk of developing cancer other than leukemia remains high sincethe other cells in her body still contain mutations in FANCC.Importance of a Matched Donor2 year survival rates vary for FA patients who have received BMTsmatched sibling donor - 66 - 85%match from bank 22 - 40%What does a matched donor mean?Our cells have molecules on their surface called human leukocyteantigens (HLA).Our immune system uses to these molecules to distinguish betweenour cells and invaders.These molecules enable infected cells to signal and initiate animmune response.In a matched donor, the molecules on the surface of the donor cellswould be the same as those found on the surface of the recipient.Why is it important for HLA type to match?If the HLA antigens are the same between the donor and the recipient,neither with recognize the other as foreign.If the HLA antigens are different…Possibility 1The donor bone marrow cells may recognize therecipient cells as foreign and attack the recipient.This can range from mild to fatal.It is known as Graft versus Host or GVHGVH is a major risk in all BMT.Possibility 2Any remaining bone marrow cells in the recipientmay recognize the transplant as foreign and destroyit.There are two type of HLA:Major Histocompatilbility Classes I and IIMHC Class I antigens. These antigens are found on the surfaceof all nucleated cells in our body. In humans the MHC Class Iantigens are called HLA-A, HLA-B and HLA-C.MHC Class II AntigensThese antigens are found on B-cells and macrophages.In humans these antigens are HLA-D, HLA-DR, HLA-DP and HLA-DQFor transplant purposesHLA-A, HLA-B and HLA-DR antigens are the most important.Since you have two copies of the genesfor each of these antigens (one from yourmother, one from your father), there are6 antigens that need to be matched.They are all co-dominant, meaning theyare all expressed on the surface of cells.A bone marrow transplant will not usually be done unless 5 out of 6 ofthese antigens match, and 6 out of 6 is considered best.Matching of additional HLA antigens (beyond HLA-A, HLA-B and HLA-DR is optimal and reduces chances of long-term complications.HLA variabilityHLA genes are highlyvariable in humans. Thispolymorphism represents aspecies response tomaximize protection againstdiverse microorganisms.This diversity in HLAantigens makes finding atransplant donor difficult.Chances of finding a matched donorAffected child’s HLA type Frequency of HLA type inpopulationHLA-A2 10 - 30%HLA-A26 2 - 4%HLA-B44 3 - 5%HLA-B35 4 - 10%HLA-DRB1 1001 ?HLA-DRB1 0402 ?A rough estimation of the probability of any given individual beinga matched donor for the child0.2 x 0.03 x 0.04 x 0.07 x 0.05 x 0.05 = 0.00000004242 out of 1 billion people will have this HLA typeCurrently around 3 million people in bone marrow donor registryChances of creating an HLA-matched siblingAll HLA genes are located onchromosome 6Recombination between theHLA loci is relatively rareSo, chances of any given sibling beinga matched donor are just under 25%In addition, the sibling will be matchedat other HLA loci as well.To create a sibling who could serve as a donorThe case we are discussing goes beyond just HLA matching, we needto find an embryo that is FA-free and is HLA-matched.HLA matching is on chromosome 6FANCC is on chromosome 9So, we are looking at 2 chromosomes rather than one.The genotypes of the family members are shown below.What are the chances of creating an HLA-matched, FA-free embryo?JAMA


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