for Primary Immunodeficiency İLHAN TEZCAN, M.D., Ph.D. Hacettepe University Children s Hospital Division of Pediatric Immunology

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1 Hematopoietic ti Stem Cell Transplantation for Primary Immunodeficiency Disorders İLHAN TEZCAN, M.D., Ph.D. Hacettepe University Children s Hospital Division of Pediatric Immunology

2 Primary immunodeficiencies are a group of finherited it dheterogenous disorders d in which distinct components of immune system are affected. Defects may be related with development and/or functions of innate and adoptive immunity.

4 Classification of Primary Immunodeficiencies Combined T-cell and B-cell immunodeficiencies Predominantly antibody deficiencies Other well defined immunodeficiency syndromes Diseases of immune dysregulation Congenital defects of phagocyte number, function, or both Defects in innate immunity Autoinflammatory disorders Complement tdeficiencies i i J Allergy Clin Immunol 120:776, 2007

5 PRİMER İMMÜNYETMEZLİKLERİN DAĞILIMI( Stiehm PRİMER İMMÜNYETMEZLİKLERİN DAĞILIMI( Stiehm E.R.Immunologic Disorders in Infants and Children)

6 PRIMARY IMMUNODEFICIENCIES CURABLE BY STEM CELL TRANSPLANTATION SCID WAS MHC class II deficiency CHEDIAK- HIGASHI Syndrome GRISCELLI DISEASE LEUKOCYTE ADHESION DEFICIENCY CHRONIC GRANULOMATOUS DISEASE HYPER-IgM SYNDROME

7 Stem cell transplantation t ti is the treatment of choice for severe forms of primary immunodeficiencies...

9 SCID A congenital syndrome a clinical phenotype in which absence of antigen specific T and B lymphocyte immunity a variety of underlying genetic abnormalities fatal unless hematopoietic stem cell transplantation (HSCT) is performed

12 CLASSIFICATION OF SEVERE COMBINED IMMUNODEFICIENCY T-B-NK- T-B-NK+ T-B+NK- T- T+B+ B+NK+ ADA defect. RAG1/ IL-2 2R IL- ZAP-70 RAG2 gamma 7Ralpha defect defect Chain defect defect Reticular Dysgenesis Omenn Syndrom JAK3 df defect CD3 Gamma defect MHC classii defect Artemis defect PNP defect IL-2 defect

14 NORMAL T LENFOSİT SAYISI OLAN BİREY T-NK- SCID Lİ HASTA

15 Allogeneic bone marrow transplantation and HSCT give the chance to reconstitute a new donor derived immune system. Since the first application in 1968 in two patients with SCID transplantation has an fundamental role in the treatment of severe forms of primary immunodeficiencies.

16 In HLA matched sibling transplantation for SCID, the probability bilit of GVHD is low and GVHD prophylaxis with immunosuppressive drugs is usually omitted and rapid immunological i l recovery is seen. Transplanted patients show a quick clinical improvement within a few weeks after transplantation and susceptibility to severe infections is resolved.

17 KİT YAPILAN T-NK-SCID Lİ BİR HASTANIN TRANSPLANT ÖNCESİ VE +1.AYDA AYDACD3+TLENFOSİT DEĞERLERİ

18 Patient Characteristics-1 56 patients with SCID enrolled in the study 59 transplantations have been performed totally during June March 2007 in Hacettepe epe University Ihsan Dogramaci Children s Hospital

19 SCID phenotypes T-B+NK- 14, 25% T+B+NK+ 1, 2% 25, 44% T-B-NK+ 16, 29% T-B+NK+

20 T-B+NK- 14 (25%) T-B+NK+ 16 (29%) T-B-NK+ 25 (44%) T-B-NK- 1 (2.2%) T+B-NK+ 2 (4.4%) T+B+NK+ 1 (2.2%) 2%)

21 Low T Low T Low B CID Median age of diagnosis (months) 5 5 (1-72) (0-12) 7 M/F ratio 19/11 17/8 1/0 Total number

22 No. of patients Genotypically Phenotypically Haploidentical identical identical Low T Low T Low B CID Total

23 no.of patients Genotyp. Phenotyp. Haplo Identical Identical Identical BM tx PSCT(CD34) Median # Nucl. cell (x /kg) CD34(x10 92 /kg) 9.2 >1 stem cell Tx Median age at tx (months) Median follow up(months) (0,5-69) (3,5-90) (3-24) (1,5-130) ( ) (2-96)

24 No of patients Tx type GVHD BO BCG Exitus Alive Inf. HLA Identic Haplo Identic 6(%40) Total # (%66) % (16) (5.3) (7.1) (41) (59)

25 The overall survival rate in SCID patients ( n: 475 total ) after HLA-identical HSCT is 77% comparing 54% after HLA mismatched HSCT. In HLA mismatched transplantation B- SCID had poorer prognosis than B + SCID ( 36% vs. 64%). Antoine C et al. Lancet 361: 553, 2003

26 Antoine C et al Lancet 2003: 361:553 Notarangelo LD et al Curr Opin Alergy Clin Immunol 2006: 443

27 The low success rate in HLA-haploidentical transplantation tti is related ltdto the intense it T cell depletion for the prevention from GvHD which causes to delayed immune reconstitution with longer periods of increased susceptibility to infections.

28 Bone Marrow Transplantation for Severe Combined Immunodeficiency ( Grunebaum E et al. JAMA 2006: 295: 508) HLA Matched Transplantation 92.3 % ( 12/13 pts) MUD 80.5 % ( 33/41 pts) MMRD 52.5 % ( 21/ 40 )

36 Death analysis of HLA identical Tx patients Alive (%) Death (%) Age at tx <6 months >6 months (83.3) 12 (57.2) 2 (16.6) 9 (42.8) SCID pheno. B+ B (61.9) 7 (70) 8 (38.1) 3 (30) CID NK (100) 16 (64) 0 (0) 9 (36) NK- 8 6 (75) 2 (25) Pulmonary inf before tx. Yes No (64.3) 9(90) 9 (35.7) 1 (10) >3 months posttx <3 months posttx 2 (18.1) 9 (81.9)

37 NORMAL İNFANTLARDA AYLARA GÖRE MUTLAK NORMAL İNFANTLARDA AYLARA GÖRE MUTLAK LENFOSİT DEĞERLERİ(Ochs H, Smith E, Puck J. P.I.D)

38 Büyüme geriliği Ağızda moniliasis Maternal GVHD Kronik ishal Akciğer enfeksiyonu Paralitik polio Dissemine BCG enfeksiyonu Deri enfeksiyonu

39 A Case with Cernunnos defect

40 SM S. M. (KİT ), 40 günlük Kemik iliği nakliöncesi WBC: 7800/mm 3 Absolu lenfosit sayısı: 4836/mm 3 Lenfosit alt grupları (%) (mm 3 ) CD CD CD CD CD Kemik iliği nakli sonrası WBC: 8300/mm 3 Absolu lenfosit sayısı: 4482/mm 3 Lenfosit alt grupları (%) (mm 3 ) CD CD CD CD CD

41 H. Y. KİT tarihi: / Yaşı: 10 ay CD3γ ekspresyon defekti

42 Mutations in Multiple Proteins, Including the CD3 and {zeta} Chains, That Cause T-Cell Immunodeficiencies. Rudd, C. E. N Engl J Med 2006;354:

45 Olgu ay ALS: 3100 /mm3 CD3: %79 CD4: %35 CD8: %38 CD19: %12 CD16+56: %5 CD45RA: %54 CD45RO: %7 IgA:109mg/dl IgG:1070mg/dl IgM: 294mg/dl Kızamık IgG (+) KabakulakIgG (+) Rubella IgG (+) CMV IgG (+) AntiHBs (-) İn vitro lenfosit transformasyonu: N

46 Olgu ay ALS: 2720 /mm3 CD3: %76 CD4: %19 CD8: %53 CD19: %16,5 CD16+56: %33 CD45RA: %43 CD45RO: %20 IgA:233mg/dl IgG:1510 mg/dl IgM: 192mg/dl Kızamık IgG (-) KabakulakIgG (-) Rubella IgG (+) CMV IgG (+) AntiHBs (+) Pnömokok 3 serotip (+) İn vitro lenfosit transformasyonu: N

47 Olgu ay ALS: 2400/mm3 CD3: %65 CD4: %33 CD8: %36 CD19: % 20 CD16+56: %10 CD45RA: %78 CD45RO: % 18 IgA:97mg/dl IgG:1960mg/dl IgM: 314mg/dl Kızamık IgG (-) KabakulakIgG (+) Rubella IgG (+) CMV IgG (-) Anti HBs (-) Polio IgG (+) İn vitro lenfosit transformasyonu: N

48 Lancet 2003;361:553

49 O.S. 5/12 kız Trabzon Beş aylığa kadar 2 kez AOM bir kez bronşiolit geçirmiş. Vücutta makulopapüler döküntü Kronik ishal Akciğer enfeksiyonu Erkek kardeşi 8 aylık eksitus Anne baba I dreceden akraba Vücut ağırlığı ve boy 5 p in altında Karaciğer 8 cm ele geliyor

52 HLA DR ( CLASS II) EKSİKLİĞİ OLAN BİR HASTANIN KİT HLA-DR ( CLASS-II) EKSİKLİĞİ OLAN BİR HASTANIN KİT ÖNCESİ VE SONRASINDA HLA-DR EKSPRESYONU

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