SCID Mouse Models of Human Stem Cell Engraftment

Several characteristics of the immunoglobulin (Ig) repertoire in fetuses and adults set them apart from each other. Functionally, this translates into differences in the affinity and effectiveness of the humoral immune response between adults and the very young. At least 2 possibilities could explain these differences: (1) fetal and adult lymphocyte progenitors differ significantly in their potential to form a diverse repertoire, and (2) factors extrinsic to the immunoglobulin locus are more influential to the character of the repertoire. To address this we used nonobese diabetic-severe combined immunodeficient-␤ 2 microglobulin knockout (NOD/SCID/␤ 2 m ؊/؊ ) mice reconstituted with human B-cell progenitors to compare the immunoglobulin repertoire potential of human fetal, cord blood, and adult sources. We found nearly identical VH and JH gene segment use and only modest differences in the third complementarity determining region of the immunoglobulin heavy chain (HCDR3). We conclude that the repertoire potential is remarkably similar regardless of the age of the individual from which progenitors are derived. Age-related differences in the immunoglobulin repertoire and variance of B-cell responses to immunization appear to arise from selection rather than from changes in recombination of the immunoglobulin locus itself. IntroductionAge-related changes in the human humoral immune system have long been known to occur and involve the nature of the antibodies that form the primary effectors of B-cell-mediated immunity. Both fetuses and older adults exhibit properties in their immunoglobulin (Ig) repertoire that differ from that seen in young adults.Neonates are vulnerable to certain pathogens and respond poorly to immunization, even though they (and fetuses) display some degree of immunologic competence. [1][2][3] This could reflect the immaturity of lymphocytes and antigen-presenting cells, or could be a result of persisting immunosuppressive aspects of the fetal environment. [4][5][6] In general the fetal repertoire is more restricted than the adult repertoire. [7][8][9] Several studies have shown that there are significant differences between the fetal, cord blood, and adult immunoglobulin repertoires in mice and humans. 8,[10][11][12][13][14][15][16][17][18][19][20][21] In humans, the VH4 family is represented throughout life but continues to increase as a function of age (particularly the VH4-34 and VH4-59 gene segments). 16 Developmental age-related changes in the third complementarity determining region of the immunoglobulin heavy chain (HCDR3) are even more dramatic, as length, for example, increases with age. The DHQ52 gene segment is commonly used in fetal sequences but is rarely found in adults. HCDR3 length is markedly reduced in fetal compared with adult sequences. 7,14,20,22 D and J gene segment preferences, as well as N nucleotide additions and exonuclease activity, account for this difference. These findings suggest that the antigen receptors on fetal B lymphocytes have a much more restricted range ...

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“…Several types of immunodeficient mice have successfully received transplants of human cells (reviewed in Greiner et al 29 ).…”

Section: Introductionmentioning

confidence: 99%

Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire

Kolar

Yokota

Rossi

et al. 2004

Blood

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“…Many groups have utilized these human-mouse (hu/mu) hematopoietic chimeras as model systems to assess HSC biology [1][2][3][4][5][6][7][8][9]. An additional application of these hu/mu chimera models is to investigate the in vivo biology of cell types of the individual human hematopoietic lineages [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Human Hematopoietic Stem/Progenitor Cells Generate CD5⁺B Lymphoid Cells in NOD/SCID Mice

et al. 1999

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“…On the other hand, consequences of mutations in the Btk tyrosine kinase gene are more severe for humans than for mice (5,6). Observations of that kind provide impetus for animal models that would efficiently support formation of human B cells from hemopoietic stem cells and nonobese diabetic (NOD) 4 /SCID mice are extremely interesting in that context (7)(8)(9). Many laboratories have shown that B cells are formed in these animals from transplanted human stem cells (8, 10 -12), but it remains unclear how closely this engraftment reflects normal steady-state conditions.…”

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confidence: 99%

Relatively Normal Human Lymphopoiesis but Rapid Turnover of Newly Formed B Cells in Transplanted Nonobese Diabetic/SCID Mice

Rossi

Medina

Garrett

et al. 2001

The Journal of Immunology

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Human B lineage lymphocyte precursors in chimeric nonobese diabetic/SCID mice transplanted with umbilical cord blood cells were directly compared with those present in normal bone marrow. All precursor subsets were represented and in nearly normal proportions. Cell cycle activity and population dynamics were investigated by staining for the Ki-67 nuclear Ag as well as by incorporation experiments using 5-bromo-2′-deoxyuridine. Again, this revealed that human B lymphopoiesis in chimeras parallels that in normal marrow with respect to replication and progression through the lineage. Moreover, sequencing of Ig gene rearrangement products showed that a diverse repertoire of VH genes was utilized by the newly formed lymphocytes but there was no evidence for somatic hypermutation. The newly formed B cells frequently acquired the CD5 Ag and had a short life span in the periphery. Thus, all molecular requirements for normal B lymphocyte formation are present in nonobese diabetic/SCID mice, but additional factors are needed for recruitment of B cells into a fully mature, long-lived pool. The model can now be exploited to learn about species restricted and conserved environmental cues for human B lymphocyte production.

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SCID Mouse Models of Human Stem Cell Engraftment

Cited by 287 publications

References 120 publications

Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire

Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire

Human Hematopoietic Stem/Progenitor Cells Generate CD5⁺B Lymphoid Cells in NOD/SCID Mice

Relatively Normal Human Lymphopoiesis but Rapid Turnover of Newly Formed B Cells in Transplanted Nonobese Diabetic/SCID Mice

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SCID Mouse Models of Human Stem Cell Engraftment

Cited by 287 publications

References 120 publications

Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire

Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire

Human Hematopoietic Stem/Progenitor Cells Generate CD5+B Lymphoid Cells in NOD/SCID Mice

Relatively Normal Human Lymphopoiesis but Rapid Turnover of Newly Formed B Cells in Transplanted Nonobese Diabetic/SCID Mice

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Human Hematopoietic Stem/Progenitor Cells Generate CD5⁺B Lymphoid Cells in NOD/SCID Mice