scholarly journals Studies of allogeneic bone marrow and spleen cell transplantation in a murine model using ultraviolet-B light

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 2072-2078 ◽  
Author(s):  
DH Pamphilon ◽  
AA Alnaqdy ◽  
V Godwin ◽  
AW Preece ◽  
TB Wallington
Keyword(s):  
Bone Marrow ◽  
Cell Damage ◽  
Lymphocyte Culture ◽  
Ultraviolet B ◽  
Allogeneic Bone ◽  
Cell Recovery ◽  
F1 Hybrid ◽  
Graft Versus Host

Abstract Ultraviolet irradiation inhibits alloreactive and mitogen-induced responses and might reduce both graft-versus-host and host-versus-graft reactions after bone marrow transplantation (BMT). We have studied proliferative responses to mitogens and reactivity in mixed lymphocyte culture after irradiation with ultraviolet (UV)-B light using splenocytes from Balb/c (H-2d) and CBA (H-2k) mice. Response to mitogens and in MLC was strongly inhibited by 20 J/m2 and abolished at 50 J/m2. Clonogenic cell recovery (CFU-GM; CFU-S) after UV-B irradiation was also reduced. When bone marrow and spleen cells were transplanted from parent (Balb/c) animals into F1 hybrid (Balb/c X CBA) recipients, all animals died with features indicative of graft-versus- host disease (GVHD) in 34 days. If the grafts were first irradiated with 100 J/m2 of UV-B at a mean wavelength of 310 nm, then 76% survived to day 80 when they were killed and shown to have normal marrow cellularity. The remainder died in marrow aplasia or of GVHD. H-2 typing in a group of surviving recipients showed either donor hematopoiesis only (8 of 15), mixed allogeneic chimerism (5 of 15), or recipient type hematopoiesis (2 of 15). Higher doses (200 to 300 J/m2) were detrimental to survival with 88% of recipients dying in marrow aplasia. Syngeneic BMT in Balb/c mice showed slower hematopoietic reconstitution when the grafts were first irradiated with 100 J/m2. After BMT from Balb/c to CBA mice all recipients of unirradiated grafts died within 54 days. By contrast, after graft irradiation with 100 J/m2 survival of recipient animals to day 80 was 59%. If these grafts were treated with 50 J/m2 survival was only 26% with an increase in deaths due to GVHD. Hematopoiesis at day 80 in a group of survivors studied by Ig heavy chain allotyping indicated donor type hematopoiesis in 6 of 10 (50 J/m2) and 2 of 9 (100 J/m2). These data indicate that UV-B irradiation inhibits lymphocyte reactivity and can prevent GVHD. However, there is clear in vitro and in vivo evidence of stem cell damage, such that autologous marrow recovery was demonstrated in a proportion of recipients. In parent----F1 UV-irradiated transplants, sustained hematopoietic recovery was effected in the majority by donor stem cells.

scholarly journals Studies of allogeneic bone marrow and spleen cell transplantation in a murine model using ultraviolet-B light

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 2072-2078
Author(s):  
DH Pamphilon ◽  
AA Alnaqdy ◽  
V Godwin ◽  
AW Preece ◽  
TB Wallington
Keyword(s):  
Bone Marrow ◽  
Cell Damage ◽  
Lymphocyte Culture ◽  
Ultraviolet B ◽  
Allogeneic Bone ◽  
Cell Recovery ◽  
F1 Hybrid ◽  
Graft Versus Host

Ultraviolet irradiation inhibits alloreactive and mitogen-induced responses and might reduce both graft-versus-host and host-versus-graft reactions after bone marrow transplantation (BMT). We have studied proliferative responses to mitogens and reactivity in mixed lymphocyte culture after irradiation with ultraviolet (UV)-B light using splenocytes from Balb/c (H-2d) and CBA (H-2k) mice. Response to mitogens and in MLC was strongly inhibited by 20 J/m2 and abolished at 50 J/m2. Clonogenic cell recovery (CFU-GM; CFU-S) after UV-B irradiation was also reduced. When bone marrow and spleen cells were transplanted from parent (Balb/c) animals into F1 hybrid (Balb/c X CBA) recipients, all animals died with features indicative of graft-versus- host disease (GVHD) in 34 days. If the grafts were first irradiated with 100 J/m2 of UV-B at a mean wavelength of 310 nm, then 76% survived to day 80 when they were killed and shown to have normal marrow cellularity. The remainder died in marrow aplasia or of GVHD. H-2 typing in a group of surviving recipients showed either donor hematopoiesis only (8 of 15), mixed allogeneic chimerism (5 of 15), or recipient type hematopoiesis (2 of 15). Higher doses (200 to 300 J/m2) were detrimental to survival with 88% of recipients dying in marrow aplasia. Syngeneic BMT in Balb/c mice showed slower hematopoietic reconstitution when the grafts were first irradiated with 100 J/m2. After BMT from Balb/c to CBA mice all recipients of unirradiated grafts died within 54 days. By contrast, after graft irradiation with 100 J/m2 survival of recipient animals to day 80 was 59%. If these grafts were treated with 50 J/m2 survival was only 26% with an increase in deaths due to GVHD. Hematopoiesis at day 80 in a group of survivors studied by Ig heavy chain allotyping indicated donor type hematopoiesis in 6 of 10 (50 J/m2) and 2 of 9 (100 J/m2). These data indicate that UV-B irradiation inhibits lymphocyte reactivity and can prevent GVHD. However, there is clear in vitro and in vivo evidence of stem cell damage, such that autologous marrow recovery was demonstrated in a proportion of recipients. In parent----F1 UV-irradiated transplants, sustained hematopoietic recovery was effected in the majority by donor stem cells.

Human Mesenchymal Stem Cells Attenuate Graft-Versus-Host Disease and Maintain Graft-Versus-Leukemia in Murine Allogeneic Bone Marrow Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1907-1907 ◽  
Author(s):  
Jeffery J Auletta ◽  
Saada Eid ◽  
Matthew Keller ◽  
Leland Metheny ◽  
Rocio Guardia-Wolff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Graft Versus Leukemia

Abstract Abstract 1907 Defining in vivo effects and biodistribution of human bone marrow-derived mesenchymal stem cell (hMSCs) following allogeneic bone marrow transplantation (alloBMT) could impact the clinical utility of MSC therapy for the prevention and treatment of graft-versus-host disease (GvHD). Using an established model of murine alloBMT, we defined hMSC effects on GvHD and graft-versus-leukemia (GvL) activity. We first studied whether hMSC could modulate in vitro murine T-cell (TC) alloreactivity in mixed leukocyte cultures (MLCs). Specifically, hMSCs added to MLCs significantly reduced TC proliferation in a concentration-dependent manner distinct from human fibroblasts. In contrast to MLC cultures alone, MLCs containing hMSCs had significant reduction in TNFα, IFNγ, and IL-10 levels and higher levels of PGE2 and TGFβ1. Modulation in the inflammatory milieu was associated with changes in TC phenotypes, including more naïve and less activated TC surface marker expression (CD62L+CD69−) and the induction of CD4+CD25+FoxP3+ T-regulatory cells. To determine whether hMSCs could modulate in vivo mTC alloreactivity, irradiated recipient B6D2F1 (H-2bxd) mice were transplanted with allogeneic C57BL/6 (H-2b) BM and purified splenic TCs (B6→B6D2F1) and then were tail-vein injected with hMSC infusions (1 million per injection) on days one and four post-transplant. Syngeneic transplant recipients (B6D2F1→B6D2F1) were used as controls. hMSC-treated alloBMT mice had significantly prolonged survival and improved clinical GvHD scores, reduced splenic TC expansion and TNFα and IFNγ-producing TCs, and lower circulating TNFα and IFNγ levels versus untreated alloBMT mice. Bioluminescence imaging showed redistribution of labeled hMSCs from the lungs to abdominal organs within 72 hours following infusion. Importantly, GvHD target tissues (small and large bowel and liver) harvested from hMSC-treated alloBMT mice had significantly lower GvHD pathology scores than untreated alloBMT mice. We next determined the effects of hMSCs on GvL activity using the murine mastocytoma cell line, P815 (H-2d). TCs co-cultured with hMSCs maintained potent in vitro cytotoxic T-lymphocyte (CTL) activity comparable to untreated control CTLs. After challenge with P815 tumor cells, hMSCs-treated alloBMT mice had less severe GvHD, eradication of tumor burden, and improved leukemia-free survival compared to alloBMT control mice. Lastly, indomethacin (IM) added to MLC-hMSC co-cultures significantly reversed attenuation in both murine TC alloreactivity and surface activation expression. In addition, IM administered to hMSC-treated alloBMT mice reversed hMSC-associated survival advantage, suggesting that PGE2 in part mediates hMSC immunomodulatory effects. Together, our results show that hMSC infusions effectively attenuate GvHD and maintain GvL potency in alloBMT mice and reveal potential biomarkers and mechanisms of action underlying hMSC effects. Disclosures: Solchaga: Bimemetic Therapeutics: Employment. Cooke:Amgen: Provides experimental drug and central pharmacy support for 2 trials for which I am Co-PI.

In Vitro Cultured Allogeneic Cytotoxic T Cells Mediate Hematopoietic GVHD without Gut GVHD Despite Expression of Functional LPAM (α4β7 Integrin).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1306-1306
Author(s):  
Ram Kalpatthi ◽  
Kathleen Nicol ◽  
Lindsay Hendey ◽  
Michael W. Boyer
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cytotoxic T Cells ◽  
Graft Versus Host Reaction ◽  
Control Group ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Radiation Control

Abstract Graft-versus-host disease (GVHD) remains a significant complication of allogeneic bone marrow transplantation. We and others have shown that in vitro cultured CD8 cytotoxic T cells (CTL) have attenuated GVHD compared to naïve cells, while retaining GVL activity. It has been shown that expression of α4β7 integrin on CD8 T cells is important for gut homing specificity in GVHD. Recently, retinoic acid (RA) has been shown to upregulate α4β7 expression on naïve T cells. Thus, we hypothesize that in vitro cultured CTL without RA lack the ability to cause GVHD in part due to deficient α4β7 expression. We used an established murine GVHD model in which spleen and lymph node cells from B6SJL mice were stimulated with splenocytes from DBA mice and were restimulated on day 7. Cultures were supplemented with IL-2 & IL-7 with and without addition of RA (100nm) on day 2. Day 14 comparison of CTL with and without RA revealed comparable CD4 (1.7% vs 0.7% respectively) and CD8 populations (96% vs 97% respectively). Phenotyping of CTL with and without RA showed CD8 α4β7 expression of 58% and 0.8% and CD8 CCR9 53% and 10% respectively. In vitro cytotoxicity was comparable between CTL with and without RA: 51% vs 41% at an effector target ratio of 10:1 (n=3, p=0.3). Both CTL groups had comparable in vitro migration towards to SDF, IP-10 & MIP-3α (p= ns). However RA treated CTL had increased migration towards TECK (chemokine expressed in small intestine); 17.3% vs 4.6% (n=4, p=0.01) and decreased migration towards TARC (chemokine expressed in skin); 2% vs 13% (n=4, p=0.03). For in vivo homing, 107 labeled cells from each CTL with (CFSE) and without RA (TRITC) were coinjected intravenously and mice were sacrificed 16 hours later for analysis. RA treated CTL had increased homing to peyer’s patch and MLN compared to CTL without RA. [Homing index (CTLRA/CTL) 2.3 and 2.5 respectively]. This finding is exaggerated in the radiated host [Homing index (CTLRA/CTL) 15 for PP and 11 for MLN]. CTL generated with or without RA (5x106 cells each) were injected intravenously in to irradiated (600 Rads) B6D2F1 recipients (3 groups; Radiation control, CTL with and without RA). Mice were followed for clinical GVHD scores and sacrificed when moribund. CBC and histopathologic GVHD scores (Liver, skin, lung, small and large intestines) were obtained. Both CTL groups developed lethal bone marrow (BM) aplasia around day 24 as compared to radiation control group; however, clinical and histopathologic GVHD scores were similar in all groups (Table 1). Our data demonstrate that both CTL with and without RA cause a lethal hematopoietic graft versus host reaction. Despite high α4β7 and CCR9 expression, significant in vitro migration to TECK and in vivo homing to gut associated lymphoid tissues, RA treated CTL did not cause significant GVHD in gut, liver or skin. This suggests that defective gut homing alone may not be sufficient to explain the attenuated GVHD from cultured CTL. Future studies are planned to confirm these findings in other GVHD models and to elucidate the mechanisms of attenuated GVHD from cultured CTL. Table 1 (Data from Day 24 sacrifice) Parameter (Mean) Radiation control CTL CTLRA p value* * CTL or CTLRA vs Radiation control group Hb (g/dL) 12.2 3.8 3.1 0.0001 WBC x106/L 1000 300 300 0.07 Platelets x103/L 667,200 50,200 29,500 0.003 BM cells from 2 femur (106) 15.3 0.9 1.1 0.0006 Combined GVHD histology score 4.9 4.4 4.2 0.3

Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8α+ dendritic cells and reduces experimental acute graft-versus-host disease

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1825-1832 ◽  
Author(s):  
Takanori Teshima ◽  
Pavan Reddy ◽  
Kathleen P. Lowler ◽  
Mark A. KuKuruga ◽  
Chen Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone ◽  
Flt3 Ligand ◽  
Graft Versus Host ◽  
Cell Responses ◽  
Acute Graft

Recent evidence suggests that dendritic cells (DCs) can regulate and amplify immune responses. Flt3 ligand (FL)–derived DC function was tested as a stimulator of allogeneic lymphocytes in vitro and in vivo. Treatment of mice with FL dramatically expanded DC number, but DCs isolated from FL-treated mice (FL DCs) were poor stimulators of allogeneic T-cell responses in vitro. Further activation of FL DCs did not restore their stimulatory ability, and FL DCs did not suppress the stimulation of the allogeneic T cells by normal DCs. FL treatment significantly increased the CD8α+ DC subset, which appeared to be the reason for their poor stimulatory capacity. These observations were confirmed in vivo using a mouse model of acute graft-versus-host disease (GVHD) wherein host DCs play a critical role. FL treatment of recipients before allogeneic bone marrow transplantation dramatically suppressed donor T-cell responses to host antigens, thereby reducing GVHD mortality (P < .01). These data represent a novel strategy that alters host DCs and reduces acute GVHD.

scholarly journals Persistence of myeloid progenitor cells expressing BCR-ABL mRNA after allogeneic bone marrow transplantation for chronic myelogenous leukemia

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2109-2114
Author(s):  
G Pichert ◽  
EP Alyea ◽  
RJ Soiffer ◽  
DC Roy ◽  
J Ritz
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Progenitor Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Myeloid Differentiation ◽  
Allogeneic Bone

Previous studies have shown that tumor-specific bcr-abl mRNA can often be detected by polymerase chain reaction. (PCR) for months to years after allogeneic bone marrow transplantation (BMT) for chronic myelocytic leukemia (CML). Nevertheless, the presence of bcr-abl mRNA by itself does not invariably predict for clinical relapse post-BMT. This has led to the hypothesis that bcr-abl mRNA might be expressed in cells that have lost either proliferative or myeloid differentiation potential. To directly characterize the cells detected by PCR in patients with CML after allogeneic BMT, we first identified five individuals in whom PCR-positive cells could be detected at multiple times post-BMT. Bone marrow samples from these individuals were cultured in vitro and single erythroid, granulocytic, and macrophage colonies, each containing 50 to 100 cells, were examined for the presence of bcr-abl mRNA by PCR. PCR-positive myeloid colonies could be detected in four of five individuals in marrow samples obtained 5 to 56 months post-BMT. Overall, 7 of 135 progenitor cell colonies (5.2%) were found to be PCR-positive. The expression of bcr-abl mRNA appeared to be equally distributed among committed erythroid, macrophage, and granulocyte progenitors. These patients have now been followed-up for an additional 20 to 33 months from the time of progenitor cell PCR analysis but only one of these individuals has been found to have cytogenetic evidence of recurrent Ph+ cells. These results show that long-term persistence of PCR-detectable bcr-abl mRNA after allogeneic BMT can be caused by the persistence of CML-derived clonogenic myeloid precursors that have survived the BMT preparative regimen. These cells continue to have both proliferative and myeloid differentiation capacity in vitro. Nevertheless, these PCR-positive cells do not appear to either expand or differentiate in vivo for prolonged periods, suggesting the presence of mechanisms for suppression of residual clonogenic leukemia cells in vivo.

Engraftment of Severe Combined Immune Deficient Mice Receiving Allogeneic Bone Marrow Via In Utero or Postnatal Transfer

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3949-3959 ◽  
Author(s):  
Bruce R. Blazar ◽  
Patricia A. Taylor ◽  
Ron McElmurry ◽  
Lina Tian ◽  
Angela Panoskaltsis-Mortari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Adoptive Transfer ◽  
In Utero ◽  
Allogeneic Bone ◽  
Severe Combined Immune Deficiency ◽  
Graft Versus Host ◽  
In Utero Transplantation ◽  
Total Body

Abstract Although in utero transplantation (IUT) has been shown to be effective in treating human severe combined immune deficiency (SCID), the relative merit of IUT as compared with postnatal bone marrow transplantation (BMT) for SCID is unknown. Therefore, comparative studies were undertaken in mice to determine the engraftment outcome in these two settings. Because T-cell depletion (TCD) reduces graft-versus-host disease (GVHD) severity but compromises alloengraftment, studies were performed with TCD or non-TCD BM and GVHD risk was assessed using a tissue scoring system and by the adoptive transfer of splenocytes from engrafted mice into secondary recipients. Non-SCID recipients received pre-BMT irradiation to simulate those circumstances in which conditioning is required for alloengraftment. IUT recipients of non-TCD and especially TCD BM cells in general had higher levels of donor T-cell and myeloid peripheral blood (PB) engraftment than nonconditioned SCID recipients. Increased TCD or non-TCD BM cell numbers in adult SCID recipients resulted in similar levels of PB engraftment as IUT recipients. However, under these conditions, mean GVHD scores were higher than in IUT recipients. The majority of adoptive transfer recipients of splenocytes from IUT recipients were GVHD-free, consistent with the in vitro evidence of tolerance to host alloantigens. Total body irradiation (TBI)-treated mice that had the highest engraftment had evidence of thymic damage as denoted by a higher proportion of thymic and splenic T cells with a memory phenotype as compared with IUT recipients. IUT mice had vigorous thymic reconstitution by 3 weeks of age. Our data indicate that IUT has a number of advantages as compared with postnatal BMT. Future studies examining the fine specificity of immunoreconstitution in IUT versus postnatal BMT are indicated.

scholarly journals Pretreatment of murine donor grafts with L-leucyl-L-leucine methyl ester: elimination of graft-versus-host disease without detrimental effects on engraftment

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 798-805 ◽  
Author(s):  
BR Blazar ◽  
DL Thiele ◽  
DA Vallera
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Methyl Ester ◽  
Graft Versus Host Disease ◽  
Host Cells ◽  
Host Disease ◽  
Murine Bone Marrow ◽  
Graft Versus Host

Abstract Incubation of murine bone marrow and splenocytes with the dipeptide methyl ester, L-leucyl-L-leucine methyl ester (Leu-Leu-OMe), which results in the selective depletion of cytotoxic T cells and their precursors, natural killer cells, and monocytes, completely protected 30 recipients of fully allogeneic donor grafts from lethal graft-versus- host disease (GVHD). These results were comparable with those obtained in 30 recipients of anti-Thy 1.2 plus complement (C')-treated donor marrow. However, in contrast to antibody- and C'-dependent T-cell depletion, which reduces the level of donor cell engraftment in our model system, we did not observe such effects using Leu-Leu-OMe marrow pretreatment. As compared with the 24 H-2 typed recipients of anti-Thy 1.2 + C'-treated donor grafts, the 29 H-2 typed recipients of Leu-Leu- OMe-treated donor grafts had significantly (P less than .001) higher percentages of donor cells (mean = 93% v 74%) and significantly (P less than .001) lower percentages of host cells (mean = 6% v 15%) posttransplantation. In vitro limiting dilution assay (LDA) was performed to assess the comparative efficacy of cytolytic T-lymphocyte (CTL) precursor depletion by Leu-Leu-OMe or anti-Thy 1.2 + C' pretreatment. We observed greater levels of CTL precursor depletion in Leu-Leu-OMe treated as compared with anti-Thy 1.2 + C'-treated bone marrow plus spleen cells (BMS) obtained from nontransplanted mice. This suggests that the in vivo results cannot simply be attributed to a less efficacious functional inactivation of cytolytic T-cell precursors by Leu-Leu-OMe treatment as compared with anti-Thy 1.2 + C' treatment. Immunoreconstitution was similar in recipients of Leu-Leu-OMe-treated grafts and anti-Thy 1.2 + C'-treated grafts 100 days posttransplant. In our opinion, Leu-Leu-OMe marrow pretreatment deserves further investigation as a methodology to achieve GVHD prevention without significantly reducing the propensity toward host cell repopulation.

scholarly journals Maintenance of hemopoietic stem cells and production of differentiated progeny in allogeneic and semiallogeneic bone marrow chimeras in vitro.

1977 ◽  
Vol 145 (6) ◽  
pp. 1612-1616 ◽  
Author(s):  
T M Dexter ◽  
M A Moore ◽  
A P Sheridan
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Culture System ◽  
Adherent Cells ◽  
Cellular Mechanisms ◽  
Graft Versus Host ◽  
Proliferation And Differentiation ◽  
Bone Marrow Chimeras

A culture system is described in which bone marrow-derived adherent cells can support prolonged proliferation and differentiation of genetically incompatible stem cells and precursor cells. The results suggest that the reactive cells responsible in vivo for host transplantation resistance and for graft-versus-host disease are selectively lost or inhibited in such cultures, which may provide a vehicle for studying some of the cellular mechanisms involved in transplantation resistance.

Engraftment of Severe Combined Immune Deficient Mice Receiving Allogeneic Bone Marrow Via In Utero or Postnatal Transfer

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3949-3959 ◽  
Author(s):  
Bruce R. Blazar ◽  
Patricia A. Taylor ◽  
Ron McElmurry ◽  
Lina Tian ◽  
Angela Panoskaltsis-Mortari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Adoptive Transfer ◽  
In Utero ◽  
Allogeneic Bone ◽  
Severe Combined Immune Deficiency ◽  
Graft Versus Host ◽  
In Utero Transplantation ◽  
Total Body

Although in utero transplantation (IUT) has been shown to be effective in treating human severe combined immune deficiency (SCID), the relative merit of IUT as compared with postnatal bone marrow transplantation (BMT) for SCID is unknown. Therefore, comparative studies were undertaken in mice to determine the engraftment outcome in these two settings. Because T-cell depletion (TCD) reduces graft-versus-host disease (GVHD) severity but compromises alloengraftment, studies were performed with TCD or non-TCD BM and GVHD risk was assessed using a tissue scoring system and by the adoptive transfer of splenocytes from engrafted mice into secondary recipients. Non-SCID recipients received pre-BMT irradiation to simulate those circumstances in which conditioning is required for alloengraftment. IUT recipients of non-TCD and especially TCD BM cells in general had higher levels of donor T-cell and myeloid peripheral blood (PB) engraftment than nonconditioned SCID recipients. Increased TCD or non-TCD BM cell numbers in adult SCID recipients resulted in similar levels of PB engraftment as IUT recipients. However, under these conditions, mean GVHD scores were higher than in IUT recipients. The majority of adoptive transfer recipients of splenocytes from IUT recipients were GVHD-free, consistent with the in vitro evidence of tolerance to host alloantigens. Total body irradiation (TBI)-treated mice that had the highest engraftment had evidence of thymic damage as denoted by a higher proportion of thymic and splenic T cells with a memory phenotype as compared with IUT recipients. IUT mice had vigorous thymic reconstitution by 3 weeks of age. Our data indicate that IUT has a number of advantages as compared with postnatal BMT. Future studies examining the fine specificity of immunoreconstitution in IUT versus postnatal BMT are indicated.

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