Hematopoietic ti Stem Cell Transplantation for Primary Immunodeficiency Disorders İLHAN TEZCAN, M.D., Ph.D. Hacettepe University Children s Hospital Division of Pediatric Immunology
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.
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
PRİMER İMMÜNYETMEZLİKLERİN DAĞILIMI( Stiehm PRİMER İMMÜNYETMEZLİKLERİN DAĞILIMI( Stiehm E.R.Immunologic Disorders in Infants and Children)
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
Stem cell transplantation t ti is the treatment of choice for severe forms of primary immunodeficiencies...
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
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
NORMAL T LENFOSİT SAYISI OLAN BİREY T-NK- SCID Lİ HASTA
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.
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.
KİT YAPILAN T-NK-SCID Lİ BİR HASTANIN TRANSPLANT ÖNCESİ VE +1.AYDA AYDACD3+TLENFOSİT DEĞERLERİ
Patient Characteristics-1 56 patients with SCID enrolled in the study 59 transplantations have been performed totally during June 1994- March 2007 in Hacettepe epe University Ihsan Dogramaci Children s Hospital
SCID phenotypes T-B+NK- 14, 25% T+B+NK+ 1, 2% 25, 44% T-B-NK+ 16, 29% T-B+NK+
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%)
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 30 25 1
No. of patients Genotypically Phenotypically Haploidentical identical identical Low T 17 8 5 Low T 11 4 10 Low B CID 1 - - Total 29 12 15
no.of patients Genotyp. Phenotyp. Haplo Identical Identical Identical BM tx 24 11 - PSCT(CD34) 5 1 15 Median # Nucl. cell (x10 8 7 8 /kg) CD34(x10 92 /kg) 9.2 >1 stem cell 1 1 1 Tx Median age at tx (months) Median follow up(months) 6 6 8 (0,5-69) (3,5-90) (3-24) 34 2 20 (1,5-130) (0.5-110) (2-96)
No of patients Tx type GVHD BO BCG Exitus Alive Inf. HLA Identic 5 2 3 14 Haplo 4 1 1 9 Identic 6(%40) Total # 9 3 4 23 33 27(%66) % (16) (5.3) (7.1) (41) (59)
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
Antoine C et al Lancet 2003: 361:553 Notarangelo LD et al Curr Opin Alergy Clin Immunol 2006: 443
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.
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 )
Death analysis of HLA identical Tx patients Alive (%) Death (%) Age at tx <6 months >6 months 12 21 10 (83.3) 12 (57.2) 2 (16.6) 9 (42.8) SCID pheno. B+ B- 21 10 13 (61.9) 7 (70) 8 (38.1) 3 (30) CID NK+ 2 25 2 (100) 16 (64) 0 (0) 9 (36) NK- 8 6 (75) 2 (25) Pulmonary inf before tx. Yes No 23 10 14 (64.3) 9(90) 9 (35.7) 1 (10) >3 months posttx <3 months posttx 2 (18.1) 9 (81.9)
NORMAL İNFANTLARDA AYLARA GÖRE MUTLAK NORMAL İNFANTLARDA AYLARA GÖRE MUTLAK LENFOSİT DEĞERLERİ(Ochs H, Smith E, Puck J. P.I.D)
Büyüme geriliği Ağızda moniliasis Maternal GVHD Kronik ishal Akciğer enfeksiyonu Paralitik polio Dissemine BCG enfeksiyonu Deri enfeksiyonu
A Case with Cernunnos defect
SM S. M. (KİT 4.09.2002), 40 günlük Kemik iliği nakliöncesi WBC: 7800/mm 3 Absolu lenfosit sayısı: 4836/mm 3 Lenfosit alt grupları (%) (mm 3 ) CD3 15 132 CD4 11.3 99 CD8 36 386 CD16-56 36 316 CD19 7.7 67 Kemik iliği nakli sonrası WBC: 8300/mm 3 Absolu lenfosit sayısı: 4482/mm 3 Lenfosit alt grupları (%) (mm 3 ) CD3 71 3227 CD4 42 1882 CD8 28 1254 CD16-56 10 448 CD19 20 896
H. Y. KİT tarihi:7.06.2005/10.11.2005 Yaşı: 10 ay CD3γ ekspresyon defekti
Mutations in Multiple Proteins, Including the CD3 and {zeta} Chains, That Cause T-Cell Immunodeficiencies. Rudd, C. E. N Engl J Med 2006;354:1874-1877
Olgu 1 +161. 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
Olgu 2 +122. 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
Olgu 3 +130. 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
Lancet 2003;361:553
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
HLA DR ( CLASS II) EKSİKLİĞİ OLAN BİR HASTANIN KİT HLA-DR ( CLASS-II) EKSİKLİĞİ OLAN BİR HASTANIN KİT ÖNCESİ VE SONRASINDA HLA-DR EKSPRESYONU