Clinical Focus

  • Immunology and Rheumatology
  • Rheumatology
  • Bone Marrow and Organ Transplantation

Academic Appointments

Professional Education

  • Internship:Massachusetts General Hospital (1967) MA
  • Residency:Stanford University School of Medicine (1971) CA
  • Fellowship:Oxford University (1965) UK
  • Residency:Massachusetts General Hospital (1967) MA
  • Medical Education:Harvard Medical School (1966) MA

Research & Scholarship

Current Research and Scholarly Interests

Research Interests:
Our interests are in the area of cellular immunology, and the regulatory interactions between subpopulations of immune cells. In particular, we are interested in the identification, function, and molecular mechanisms by which some subpopulations of lymphocytes amplify the immune response and some such as natural killer T cells (NKT cells) and regulatory T cells (Treg cells) suppress it. Investigation into interactions of the cells during the immune response to organ and bone marrow transplants and in tumor immunity is a major focus of the laboratory research. Developing therapeutic strategies for clinical organ transplantation in humans with hematologic or solid tumors based on these principles is a major goal. Specific areas of research are as follows:

(i) Immune tolerance to organ and bone marrow transplants: Immune tolerance is recognized to be the paralysis of the immune system in its response to a given antigen, the development of anergy, or antigen-specific suppressor cells. Our research programs are studying these mechanisms at the cellular and molecular levels in laboratory animals and humans that are made tolerant to foreign organ or bone marrow transplants. In the case of bone marrow transplants, the goal is to prevent graft vs. host disease while maintaining graft anti-tumor activity.

(ii) In the case of organ transplants, the goal is to achieve acceptance of the transplants in the absence of maintenance immonosuppressive drugs. Tolerance is achieved by establishment of mixed chimerism. Our mouse models have been translated to clinical studies in which tolerance and prevention of graft vs host disease have been achieved. Our laboratory is involved in identifying those cells (NKTcells, Treg cells, myeloid derived suppressor cells, dendritic cells) involved in the induction and maintenance of immune tolerance with regard to their surface receptors, effector functions, and the nature of secreted molecules which mediate their function. We have shown that interactions of these cells are important suppressors of tumor immunity and promoters of organ transplantation tolerance.

Clinical Trials

  • TLI & ATG for Non-Myeloablative Allogeneic Transplantation for MDS and MPD Not Recruiting

    To evaluate the feasibility and safety of TLI/ATG conditioning for allogeneic HCT for elderly patients with advanced stage MDS and MPD.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Allogeneic Transplantation From Related Haploidentical Donors in Older Patients With Indolent Hematologic Malignancies Not Recruiting

    The purpose of the study is to evaluate the feasibility and safety of transplanting CD34+ selected hematopoietic cells from a haploidentical related donor following a nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG).

    Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, (650) 723 - 0822.

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  • Immunostimulatory CpG SD-101 + RT in Recurrent/Progressive Lymphoma After Allogeneic Hematopoietic Cell Transplantation (HCT) Not Recruiting

    For patients with lymphoma that recurs after chemotherapy, bone marrow transplantation using cells from a healthy donor represents potentially curative treatment. In these individuals, cure is possible because transplantation of healthy donor immune cells can fight the lymphoma in the patient. The goal of this work is to test a strategy that activates the healthy donor immune cells so that they more effectively fight lymphoma and can result in anincreased cure rate for these patients. Our group has previously studied CpG, an immune activating medication, in patients with lymphoma and demonstrated modest anti-tumor responses. We now have a more potent form of CpG which we intend to test to see if it will better activate the donor immune cells and result in shrinkage of tumor throughout the entire body, not just at the injected site.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Combined Blood Stem Cell and Kidney Transplant of One Haplotype Match Living Donor Pairs. Recruiting

    The Stanford Medical Center Program in Multi-Organ Transplantation and the Division of Bone marrow Transplantation are enrolling patients into a research study to determine if donor stem cells given after a living related one Haplotype match kidney transplantation will change the immune system such that immunosuppressive drugs can be completely withdrawn.

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  • Donor Peripheral Stem Cell Transplant in Treating Patients With Hematolymphoid Malignancies Recruiting

    This phase I trial studies the side effects and the best dose of donor CD8+ memory T-cells in treating patients with hematolymphoid malignancies. Giving low dose of chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-cancer effects). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect

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2014-15 Courses

Graduate and Fellowship Programs


All Publications

  • Treatment of 4T1 metastatic breast cancer tumors with combined hypofractionated radiation and autologous T cell transplantation infusion Radiation Research Filatenkov, A., Baker, J., Ahn, G. O., Kohrt, H., Dutt, S., Dejbakhsh-Jones, S., Negrin, R. S., Engleman, E. G., Strober, S. 2014; 182 (2): 163-169
  • Requirement for interactions of natural killer T cells and myeloid derived suppressor cells for transplantation tolerance AJT Hongo, D., Tang, X., Baker, J., Engleman, E. G., Strober, s. 2014; 14 (11): 2467-77
  • Chimerism, graft survival, and withdrawal of immunosupressive drugs in HLA matched and mismatched patients after kidney and hematopoietic cell transplantation AJT Scandling, J. D., Busque, S., Shizuru, J. A., Lowsky, R., Hoppe, R., Dejbakhsh-Jones, S., Jensen, K., Shori, A., Strober, J. A., Lavori, P., Turnbull, B. B., Engleman, E. G., Strober, S. 2014
  • Ly108 expression distinguishes subsets of invariant NKT cells that help autoantibody production and secrete IL-21 from those that secrete IL-17 in lupus prone NZB/W mice J Autoimmun Tang, X., Jarrell, J. A., Price, J. V., Dai, H., Utz, P. J., Strober, S. 2014; 50: 87-98
  • Path to clinical transplantation tolerance and prevention of graft versus host disease. Immunologic Research Strober, S. 2014; 58 (2-3): 240-8
  • Identification of gene microarray expression profiles in patients with chronic graft-versus-host disease following allogeneic hematopoietic cell transplantation CLINICAL IMMUNOLOGY Kohrt, H. E., Tian, L., Li, L., Alizadeh, A. A., Hsieh, S., Tibshirani, R. J., Strober, S., Sarwal, M., Lowsky, R. 2013; 148 (1): 124-135


    Chronic graft-versus-host disease (GVHD) results in significant morbidity and mortality, limiting the benefit of allogeneic hematopoietic cell transplantation (HCT). Peripheral blood gene expression profiling of the donor immune repertoire following HCT may provide associated genes and pathways thereby improving the pathophysiologic understanding of chronic GVHD. We profiled 70 patients and identified candidate genes that provided mechanistic insight in the biologic pathways that underlie chronic GVHD. Our data revealed that the dominant gene signature in patients with chronic GVHD represented compensatory responses that control inflammation and included the interleukin-1 decoy receptor, IL-1 receptor type II, and genes that were profibrotic and associated with the IL-4, IL-6 and IL-10 signaling pathways. In addition, we identified three genes that were important regulators of extracellular matrix. Validation of this discovery phase study will determine if the identified genes have diagnostic, prognostic or therapeutic implications.

    View details for DOI 10.1016/j.clim.2013.04.013

    View details for Web of Science ID 000320427300015

  • Characterization of direct radiation-induced immune function and molecular signaling changes in an antigen presenting cell line CLINICAL IMMUNOLOGY Parker, J. J., Jones, J. C., Strober, S., Knox, S. J. 2013; 148 (1): 44-55


    Radiation therapy is a widely used cancer treatment and pre-transplantation conditioning regimen that has the potential to influence anti-tumor and post-transplantation immune responses. Although conventionally fractionated radiation doses can suppress immune responses by depleting lymphocytes, single high doses of local tumor radiation can enhance immune responses. Using phospho-flow cytometry analysis of a human monocytic cell line, we identified novel radiation-induced changes in the phosphorylation state of NFκB family members known in other cell types to maintain and regulate immune function. These phosphorylation changes were p53 independent, but were strongly dependent upon ATM activation due to DNA damage. We found that radiation promotes the activation and APC functional maturation through phosphorylation of NFκB Essential Modulator (NEMO). Our results and the analytic methods are especially well suited to the study of functional changes in APC when radiation is used for immune modulation in clinical protocols.

    View details for DOI 10.1016/j.clim.2013.03.008

    View details for Web of Science ID 000320427300006

    View details for PubMedID 23649044

  • Uniform Long-Term Graft Survival in a Clincial Trial of the Induction of Tolerance to Kidney Transplants. Scandling, J., Busque, S., Shori, A., Dejbakhsh-Jones, S., Shizuru, J., Lowsky, R., Benike, C., Engleman, E., Strober, S. WILEY-BLACKWELL. 2013: 200-200
  • A distinct evolution of the T-cell repertoire categorizes treatment refractory gastrointestinal acute graft-versus-disease Blood Meyer, E. H., Hsu, A. R., Liliental, J., Lohr, A., Zehnder, M., Strober, S., Lavori, P., Miklos, D. B., Johnson, D. S., Negrin, R. S. 2013; 121 (24): 4955-4962
  • Rare cells predict GVHD. Blood Strober, S., Lowsky, R. 2012; 119 (21): 4820-4821

    View details for DOI 10.1182/blood-2012-04-417311

    View details for PubMedID 22627595

  • Tolerance and Withdrawal of Immunosuppressive Drugs in Patients Given Kidney and Hematopoietic Cell Transplants AMERICAN JOURNAL OF TRANSPLANTATION Scandling, J. D., Busque, S., Dejbakhsh-Jones, S., Benike, C., Sarwal, M., Millan, M. T., Shizuru, J. A., Lowsky, R., Engleman, E. G., Strober, S. 2012; 12 (5): 1133-1145


    Sixteen patients conditioned with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) were given kidney transplants and an injection of CD34+ hematopoietic progenitor cells and T cells from HLA-matched donors in a tolerance induction protocol. Blood cell monitoring included changes in chimerism, balance of T-cell subsets and responses to donor alloantigens. Fifteen patients developed multilineage chimerism without graft-versus-host disease (GVHD), and eight with chimerism for at least 6 months were withdrawn from antirejection medications for 1-3 years (mean, 28 months) without subsequent rejection episodes. Four chimeric patients have just completed or are in the midst of drug withdrawal, and four patients were not withdrawn due to return of underlying disease or rejection episodes. Blood cells from all patients showed early high ratios of CD4+CD25+ regulatory T cells and NKT cells versus conventional naive CD4+ T cells, and those off drugs showed specific unresponsiveness to donor alloantigens. In conclusion, TLI and ATG promoted the development of persistent chimerism and tolerance in a cohort of patients given kidney transplants and hematopoietic donor cell infusions. All 16 patients had excellent graft function at the last observation point with or without maintenance drugs.

    View details for DOI 10.1111/j.1600-6143.2012.03992.x

    View details for Web of Science ID 000303235100012

    View details for PubMedID 22405058

  • Interactions between NKT cells and Tregs are required for tolerance to combined bone marrow and organ transplants BLOOD Hongo, D., Tang, X., Dutt, S., Nador, R. G., Strober, S. 2012; 119 (6): 1581-1589


    We used a model of combined bone marrow and heart transplantation, in which tolerance and stable chimerism is induced after conditioning with fractionated irradiation of the lymphoid tissues and anti-T-cell antibodies. Graft acceptance and chimerism required host CD4(+)CD25(+) Treg production of IL-10 that was in-turn enhanced by host invariant natural killer (NK) T-cell production of IL-4. Up-regulation of PD-1 on host Tregs, CD4(+)CD25(-) conventional T (Tcon) cells, and CD8(+) T cells was also enhanced by NKT cell production of IL-4. Up-regulated PD-1 expression on Tregs was linked to IL-10 secretion, on CD8(+) T cells was linked to Tim-3 expression, and on CD4(+) Tcon cells was associated with reduced IFN? secretion. Changes in the expression of PD-1 were induced by the conditioning regimen, and declined after bone marrow transplantation. In conclusion, NKT cells in this model promoted changes in expression of negative costimulatory receptors and anti-inflammatory cytokines by Tregs and other T-cell subsets in an IL-4-dependent manner that resulted in tolerance to the bone marrow and organ grafts.

    View details for DOI 10.1182/blood-2011-08-371948

    View details for Web of Science ID 000300420900035

    View details for PubMedID 22174155

  • Donor immunization with WT1 peptide augments antileukemic activity after MHC-matched bone marrow transplantation BLOOD Kohrt, H. E., Mueller, A., Baker, J., Goldstein, M. J., Newell, E., Dutt, S., Czerwinski, D., Lowsky, R., Strober, S. 2011; 118 (19): 5319-5329


    The curative potential of MHC-matched allogeneic bone marrow transplantation (BMT) is in part because of immunologic graft-versus-tumor (GvT) reactions mediated by donor T cells that recognize host minor histocompatibility antigens. Immunization with leukemia-associated antigens, such as Wilms Tumor 1 (WT1) peptides, induces a T-cell population that is tumor antigen specific. We determined whether allogeneic BMT combined with immunotherapy using WT1 peptide vaccination of donors induced more potent antitumor activity than either therapy alone. WT1 peptide vaccinations of healthy donor mice induced CD8(+) T cells that were specifically reactive to WT1-expressing FBL3 leukemia cells. We found that peptide immunization was effective as a prophylactic vaccination before tumor challenge, yet was ineffective as a therapeutic vaccination in tumor-bearing mice. BMT from vaccinated healthy MHC-matched donors, but not syngeneic donors, into recipient tumor-bearing mice was effective as a therapeutic maneuver and resulted in eradication of FBL3 leukemia. The transfer of total CD8(+) T cells from immunized donors was more effective than the transfer of WT1-tetramer(+)CD8(+) T cells and both required CD4(+) T-cell help for maximal antitumor activity. These findings show that WT1 peptide vaccination of donor mice can dramatically enhance GvT activity after MHC-matched allogeneic BMT.

    View details for DOI 10.1182/blood-2011-05-356238

    View details for Web of Science ID 000296867100035

  • Selective Resistance of CD44(hi) T Cells to p53-Dependent Cell Death Results in Persistence of Immunologic Memory after Total Body Irradiation JOURNAL OF IMMUNOLOGY Yao, Z., Jones, J., Kohrt, H., Strober, S. 2011; 187 (8): 4100-4108


    Our previous studies showed that treatment of mice with total body irradiation (TBI) or total lymphoid tissue irradiation markedly changes the balance of residual T cell subsets to favor CD4(+)CD44(hi) NKT cells because of the differential resistance of the latter subset to cell death. The object of the current study was to further elucidate the changed balance and mechanisms of differential radioresistance of T cell subsets after graded doses of TBI. The experimental results showed that CD4(+) T cells were markedly more resistant than CD8(+) T cells, and CD44(hi) T cells, including NKT cells and memory T cells, were markedly more resistant than CD44(lo) (naive) T cells. The memory T cells immunized to alloantigens persisted even after myeloablative (1000 cGy) TBI and were able to prevent engraftment of bone marrow transplants. Although T cell death after 1000 cGy was prevented in p53(-/-) mice, there was progressive T cell death in p53(-/-) mice at higher doses. Although p53-dependent T cell death changed the balance of subsets, p53-independent T cell death did not. In conclusion, resistance of CD44(hi) T cells to p53-dependent cell death results in the persistence of immunological memory after TBI and can explain the immune-mediated rejection of marrow transplants in sensitized recipients.

    View details for DOI 10.4049/jimmunol.1101141

    View details for Web of Science ID 000295623100022

    View details for PubMedID 21930972

  • Translational studies in hematopoietic cell transplantation: Treatment of hematologic malignancies as a stepping stone to tolerance induction SEMINARS IN IMMUNOLOGY Strober, S., Spitzer, T. R., Lowsky, R., Sykes, M. 2011; 23 (4): 273-281


    Allogeneic hematopoietic cell transplantation (HCT) has most commonly been used to treat hematologic malignancies, where it is often the only potentially curative option available. The success of HCT has been limited by transplant-associated toxicities related to the conditioning regimens used and to the common immunologic consequence of donor T cell recognition of recipient alloantigens, graft-vs-host disease (GVHD). The frequency and severity of GVHD observed when extensive HLA barriers are transgressed has essentially precluded the routine use of extensively HLA-mismatched HCT. Allogeneic HCT also has potential as an approach to organ allograft tolerance induction, but this potential has not been previously realized because of the toxicity associated with traditional conditioning. In this paper we review two approaches to HCT involving reduced intensity conditioning regimens that have been associated with improvements in safety in patients with hematologic malignancies, even in the HLA-mismatched transplant setting. These strategies have been applied in the first successful pilot studies for the induction of organ allograft tolerance in humans. Thus, we summarize an example of vertical translational research between animal models and humans and horizontal translation between two separate goals that culminated in the use of HCT to achieve allograft tolerance in humans.

    View details for DOI 10.1016/j.smim.2011.05.001

    View details for Web of Science ID 000296403800006

    View details for PubMedID 21705229

  • CD8(+)CD44(hi) but not CD4(+)CD44(hi) memory T cells mediate potent graft antilymphoma activity without GVHD BLOOD Dutt, S., Baker, J., Kohrt, H. E., Kambham, N., Sanyal, M., Negrin, R. S., Strober, S. 2011; 117 (11): 3230-3239


    Allogeneic hematopoietic cell transplantation can be curative in patients with leukemia and lymphoma. However, progressive growth of malignant cells, relapse after transplantation, and graft-versus-host disease (GVHD) remain important problems. The goal of the current murine study was to select a freshly isolated donor T-cell subset for infusion that separates antilymphoma activity from GVHD, and to determine whether the selected subset could effectively prevent or treat progressive growth of a naturally occurring B-cell lymphoma (BCL(1)) without GVHD after recipients were given T cell-depleted bone marrow transplantations from major histocompatibility complex-mismatched donors. Lethal GVHD was observed when total T cells, naive CD4(+) T cells, or naive CD8(+) T cells were used. Memory CD4(+)CD44(hi) and CD8(+)CD44(hi) T cells containing both central and effector memory cells did not induce lethal GVHD, but only memory CD8(+) T cells had potent antilymphoma activity and promoted complete chimerism. Infusion of CD8(+) memory T cells after transplantation was able to eradicate the BCL(1) lymphoma even after progressive growth without inducing severe GVHD. In conclusion, the memory CD8(+) T-cell subset separated graft antilymphoma activity from GVHD more effectively than naive T cells, memory CD4(+) T cells, or memory total T cells.

    View details for DOI 10.1182/blood-2010-10-312751

    View details for Web of Science ID 000288496300035

    View details for PubMedID 21239702

  • NKT cells, Treg, and their interactions in bone marrow transplantation EUROPEAN JOURNAL OF IMMUNOLOGY Kohrt, H. E., Pillai, A. B., Lowsky, R., Strober, S. 2010; 40 (7): 1862-1869


    Bone marrow transplantation (BMT) is a potentially curative treatment for patients with leukemia and lymphoma. Tumor eradication is promoted by the anti-tumor activity of donor T cells contained in the transplant; however, donor T cells also mediate the serious side effect of graft-versus-host disease (GVHD). Separation of GVHD from graft anti-tumor activity is an important goal of research in improving transplant outcome. One approach is to take advantage of the immunomodulatory activity of regulatory NKT cells and CD4(+)CD25(+) Treg of host and/or donor origin. Both host and donor NKT cells and donor Treg are able to prevent GVHD in murine models. In this review, we summarize the mechanisms of NKT cell- and Treg-mediated protection against GVHD in mice while maintaining graft anti-tumor activity. In addition, we also examine the interactions between NKT cells and Treg in the context of BMT, and integrate the data from murine experimental models with the observations made in humans.

    View details for DOI 10.1002/eji.201040394

    View details for Web of Science ID 000280220600014

    View details for PubMedID 20583031

  • Induced Tolerance to Rat Liver Allografts Involves the Apoptosis of Intragraft T Cells and the Generation of CD4(+)CD25(+)FoxP3(+) T Regulatory Cells LIVER TRANSPLANTATION Fujiki, M., Esquivel, C. O., Martinez, O. M., Strober, S., Uemoto, S., Krams, S. M. 2010; 16 (2): 147-154


    Posttransplant total lymphoid irradiation is a nonmyeloablative regimen that has been extensively studied in rodent models for the induction of tolerance to bone marrow and solid organ allografts. Previous studies of experimental models and clinical transplantation have used total lymphoid irradiation in combination with anti-lymphocyte-depleting reagents and donor cell infusion to promote graft acceptance. In a rat model of orthotopic liver transplantation, we demonstrated that total lymphoid irradiation alone induced long-term graft survival. Apoptotic T cells were detected in markedly higher numbers in the livers of the total lymphoid irradiation-treated group in comparison with the control group of liver allograft recipients. Intragraft CD4(+)CD25(+)FoxP3(+) cells were increased in the total lymphoid irradiation group in the first week post-transplant and remained elevated in the graft and in the spleen. Importantly, the adoptive transfer of splenocytes from recipients that received posttransplant total lymphoid irradiation prolonged the survival of donor heart grafts, but not third-party heart grafts, whereas the depletion of CD4(+)CD25(+) cells from transferred splenocytes abrogated this prolongation. We conclude that posttransplant total lymphoid irradiation significantly increases the apoptosis of T cells in the liver graft and allows the accumulation of CD4(+)CD25(+)FoxP3(+) T regulatory cells, which facilitate the generation of donor-specific tolerance.

    View details for DOI 10.1002/lt.21963

    View details for Web of Science ID 000274437800005

    View details for PubMedID 20104482

  • The Changed Balance of Regulatory and Naive T Cells Promotes Tolerance after TLI and Anti-T-Cell Antibody Conditioning AMERICAN JOURNAL OF TRANSPLANTATION Nador, R. G., Hongo, D., Baker, J., Yao, Z., Strober, S. 2010; 10 (2): 262-272


    The goal of the study was to determine how the changed balance of host naïve and regulatory T cells observed after conditioning with total lymphoid irradiation (TLI) and antithymocyte serum (ATS) promotes tolerance to combined organ and bone marrow transplants. Although previous studies showed that tolerance was dependent on host natural killer T (NKT) cells, this study shows that there is an additional dependence on host CD4(+)CD25(+) Treg cells. Depletion of the latter cells before conditioning resulted in rapid rejection of bone marrow and organ allografts. The balance of T-cell subsets changed after TLI and ATS with TLI favoring mainly NKT cells and ATS favoring mainly Treg cells. Combined modalities reduced the conventional naïve CD4(+) T cells 2800-fold. The host type Treg cells that persisted in the stable chimeras had the capacity to suppress alloreactivity to both donor and third party cells in the mixed leukocyte reaction. In conclusion, tolerance induction after conditioning in this model depends upon the ability of naturally occurring regulatory NKT and Treg cells to suppress the residual alloreactive T cells that are capable of rejecting grafts.

    View details for DOI 10.1111/j.1600-6143.2009.02942.x

    View details for Web of Science ID 000273884800015

    View details for PubMedID 20041865

  • Ineffective Vaccination against Solid Tumors Can Be Enhanced by Hematopoietic Cell Transplantation JOURNAL OF IMMUNOLOGY Filatenkov, A., Mueller, A. M., Tseng, W. W., Dejbakhsh-Jones, S., Winer, D., Luong, R., Shizuru, J. A., Engleman, E. G., Strober, S. 2009; 183 (11): 7196-7203


    Vaccination with tumor Ags has not been an effective treatment for solid tumors. The goal of the current study was to determine whether a combination of vaccination and hematopoietic cell transplantation (HCT) can effectively treat primary, disseminated, or metastatic CT26 and MC38 murine colon tumors. Vaccination of tumor-bearing mice with irradiated tumor cells and CpG adjuvant failed to alter progressive tumor growth. However, mice bearing primary, disseminated lung, or metastatic liver tumors were uniformly cured after administration of total body irradiation, followed by the transplantation of hematopoietic progenitor cells and T cells from syngeneic, but not allogeneic vaccinated donors. Requirements for effective treatment of tumors included irradiation of hosts, vaccination of donors with both tumor cells and CpG, transfer of both CD4(+) and CD8(+) T cells along with progenitor cells, and ability of donor cells to produce IFN-gamma. Irradiation markedly increased the infiltration of donor T cells into the tumors, and the combined irradiation and HCT altered the balance of tumor-infiltrating cells to favor CD8(+) effector memory T cells as compared with CD4(+)CD25(+)FoxP3(+) T regulatory cells. The combination of vaccination and autologous hematopoietic cell transplantation was also effective in treating tumors. In conclusion, these findings show that otherwise ineffective vaccination to solid nonhematologic tumors can be dramatically enhanced by HCT.

    View details for DOI 10.4049/jimmunol.0900159

    View details for Web of Science ID 000272478800039

    View details for PubMedID 19890041

  • beta-galactosylceramide alters invariant natural killer T cell function and is effective treatment for lupus CLINICAL IMMUNOLOGY Morshed, S. R., Takahashi, T., Savage, P. B., Kambham, N., Strober, S. 2009; 132 (3): 321-333


    NZB/W female mice spontaneously develop systemic lupus, an autoantibody mediated disease associated with immune complex glomerulonephritis. Natural killer (NK) T cells augment anti-dsDNA antibody secretion by NZB/W B cells in vitro, and blocking NKT cell activation in vivo with anti-CD1 mAb ameliorates lupus disease activity. In the current study, we show that beta-galactosylceramide reduces the in vivo induction of serum IFN-gamma and/or IL-4 by the potent NKT cell agonist alpha-galactosylceramide and reduces NKT cell helper activity for IgG secretion. Treatment of NZB/W mice with the beta-galactosylceramide ameliorated lupus disease activity as judged by improvement in proteinuria, renal histopathology, IgG anti-dsDNA antibody formation, and survival. In conclusion, beta-galactosylceramide, a glycolipid that reduces the cytokine secretion induced by a potent NKT cell agonist ameliorates lupus in NZB/W mice.

    View details for DOI 10.1016/j.clim.2009.05.018

    View details for Web of Science ID 000268783900004

    View details for PubMedID 19564135

  • TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors BLOOD Kohrt, H. E., Turnbull, B. B., Heydari, K., Shizuru, J. A., Laport, G. G., Miklos, D. B., Johnston, L. J., Arai, S., Weng, W., Hoppe, R. T., Lavori, P. W., Blume, K. G., Negrin, R. S., Strober, S., Lowsky, R. 2009; 114 (5): 1099-1109


    A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at under IDs of NCT00185640 and NCT00186615.

    View details for DOI 10.1182/blood-2009-03-211441

    View details for Web of Science ID 000268491100025

    View details for PubMedID 19423725

  • Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4(+)CD25(+)Foxp3(+) T regulatory cells that protects against graft-versus-host disease BLOOD Pillai, A. B., George, T. I., Dutt, S., Strober, S. 2009; 113 (18): 4458-4467


    Although CD4(+)CD25(+) T cells (T regulatory cells [Tregs]) and natural killer T cells (NKT cells) each protect against graft-versus-host disease (GVHD), interactions between these 2 regulatory cell populations after allogeneic bone marrow transplantation (BMT) have not been studied. We show that host NKT cells can induce an in vivo expansion of donor Tregs that prevents lethal GVHD in mice after conditioning with fractionated lymphoid irradiation (TLI) and anti-T-cell antibodies, a regimen that models human GVHD-protective nonmyeloablative protocols using TLI and antithymocyte globulin (ATG), followed by allogeneic hematopoietic cell transplantation (HCT). GVHD protection was lost in NKT-cell-deficient Jalpha18(-/-) hosts and interleukin-4 (IL-4)(-/-) hosts, or when the donor transplant was Treg depleted. Add-back of donor Tregs or wild-type host NKT cells restored GVHD protection. Donor Treg proliferation was lost in IL-4(-/-) hosts or when IL-4(-/-) mice were used as the source of NKT cells for adoptive transfer, indicating that host NKT cell augmentation of donor Treg proliferation after TLI/antithymocyte serum is IL-4 dependent. Our results demonstrate that host NKT cells and donor Tregs can act synergistically after BMT, and provide a mechanism by which strategies designed to preserve host regulatory cells can augment in vivo donor Treg expansion to regulate GVHD after allogeneic HCT.

    View details for DOI 10.1182/blood-2008-06-165506

    View details for Web of Science ID 000265846300042

    View details for PubMedID 19221040

  • Differences in Bcl-2 expression by T-cell subsets alter their balance after in vivo irradiation to favor CD4+Bcl-2(hi) NKT cells EUROPEAN JOURNAL OF IMMUNOLOGY Yao, Z., Liu, Y., Jones, J., Strober, S. 2009; 39 (3): 763-775


    Although it is well known that in vivo radiation depletes immune cells via the Bcl-2 apoptotic pathway, a more nuanced analysis of the changes in the balance of immune-cell subsets is needed to understand the impact of radiation on immune function. We show the balance of T-cell subsets changes after increasing single doses of total body irradiation (TBI) or after fractionated irradiation of the lymphoid tissues (TLI) of mice due to differences in radioresistance and Bcl-2 expression of the NKT-cell and non-NKT subsets to favor CD4(+)Bcl-2(hi) NKT cells. Reduction of the Bcl-2(lo) mature T-cell subsets was at least 100-fold greater than that of the Bcl-2(hi) subsets. CD4(+) NKT cells upregulated Bcl-2 after TBI and TLI and developed a Th2 bias after TLI, whereas non-NKT cells failed to do so. Our previous studies showed TLI protects against graft versus host disease in wild-type, but not in NKT-cell-deficient mice. The present study shows that NKT cells have a protective function even after TBI, and these cells are tenfold more abundant after an equal dose of TLI. In conclusion, differential expression of Bcl-2 contributes to the changes in T-cell subsets and immune function after irradiation.

    View details for DOI 10.1002/eji.200838657

    View details for Web of Science ID 000264683500025

    View details for PubMedID 19197937

  • Simultaneous protection against allograft rejection and graft-versus-host disease after total lymphoid irradiation: Role of natural killer T cells TRANSPLANTATION Liu, Y. P., Li, Z., Nador, R. G., Strober, S. 2008; 85 (4): 607-614


    The use of combined organ and bone marrow transplantation has been studied extensively in rodent models to induce immune tolerance to organ grafts. However, bone marrow transplants with mature donor T cells can induce graft-versus-host disease even in human leukocyte antigen-matched humans. We determined whether total lymphoid irradiation can simultaneously protect against graft-versus-host disease while facilitating tolerance.To more closely model clinical studies, we added mature donor T cells to bone marrow grafts combined with heart grafts, and compared murine graft and host survival after conditioning with nonmyeloablative total body or total lymphoid irradiation and depletive anti-T-cell antibodies.Conditioning with total lymphoid irradiation protected hosts against both graft-versus-host disease and organ graft rejection. Although nonmyeloblative total body irradiation prevented organ graft rejection, all hosts succumbed to lethal graft-versus host disease. Induction of tolerance with total lymphoid irradiation and anti-T-cell antibodies was dependent on the presence of regulatory host natural killer T cells, and expression of CD1d on donor marrow but not heart graft cells.Conditioning with total lymphoid irradiation and anti-T-cell antibodies prevented host-versus-donor and donor-versus-host alloimmune responses. Tolerance required host natural killer T-cell recognition of CD1d on donor marrow cells.

    View details for DOI 10.1097/TP.0b013e31816361ce

    View details for Web of Science ID 000253513700017

    View details for PubMedID 18347541

  • Tolerance and chimerism after renal and hematopoietic-cell transplantation. New England journal of medicine Scandling, J. D., Busque, S., Dejbakhsh-Jones, S., Benike, C., Millan, M. T., Shizuru, J. A., Hoppe, R. T., Lowsky, R., Engleman, E. G., Strober, S. 2008; 358 (4): 362-368


    We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched donor. A post-transplantation conditioning regimen of total lymphoid irradiation and antithymocyte globulin allowed engraftment of the donor's hematopoietic cells. The patient had persistent mixed chimerism, and the function of the kidney allograft has been normal for more than 28 months since discontinuation of all immunosuppressive drugs. Adverse events requiring hospitalization were limited to a 2-day episode of fever with neutropenia. The patient has had neither rejection episodes nor clinical manifestations of graft-versus-host disease.

    View details for DOI 10.1056/NEJMoa074191

    View details for PubMedID 18216356

  • Protective conditioning against GVHD and graft rejection after combined organ and hematopoietic cell transplantation BLOOD CELLS MOLECULES AND DISEASES Strober, S. 2008; 40 (1): 48-54


    We have performed combined organ and hematopoietic cell transplantation using a similar conditioning regimen in mice and humans. In the mouse model of MHC-mismatched combined heart and marrow transplantation, we compared conditioning of BALB/c hosts with total lymphoid irradiation (TLI: 10 doses of 240 cGy each) targeted to the spleen, lymph nodes and thymus to conditioning with a single dose of sublethal total body irradiation (TBI; 450 cGy). Conditioning also included three injections of anti-thymocyte serum (ATS), in both groups. C57BL/6 heart grafts, marrow cells and blood mononuclear cells were transplanted 24 h after the completion of irradiation. Blood mononuclear cells were added to the marrow cells to engender severe graft versus host disease (GVHD) that is present after combined organ and hematopoietic cell transplantation in humans given non-myeloablative conditioning. Both TLI and TBI conditioned groups accepted the organ grafts and became stable chimeras. However, the TBI group all died of GVHD during the 100-day observation period. The TLI group survived during the same period without clinical signs of GVHD. These hosts were tolerized to the donor organ grafts, since third party grafts were rejected rapidly when transplanted after 100 days. When NK T-cell-deficient CD1d(-/-) BALB/c hosts were used instead of wild-type hosts in the TLI/ATS conditioned group, then all hosts survived but all rejected the organ grafts and almost all failed to develop stable chimerism. None developed GVHD. Since host NK T cells were required for graft acceptance and NK T cells are activated after recognition of CD1d on antigen presenting cells, we compared heart and marrow graft survival from wild-type versus CD1d(-/-) donors after transplantation to TLI and ATS conditioned wild-type hosts. Whereas marrow and heart grafts from wild-type donors were accepted, almost all grafts from CD1d donors were rejected. Grafts from control Jalpha18(-/-) donors that were NK T cell deficient but expressed CD1d were all accepted. The results indicate that host NK T cells facilitate graft acceptance by recognizing CD1d on donor cells. We applied the TLI conditioning regimen using 10 doses of 80 cGy each and 5 doses of rabbit ATG to human recipients of HLA-matched G-CSF "mobilized" blood mononuclear cell transplants for the treatment of leukemia and lymphoma [R. Lowsky, T. Takahashi, Y.P. Liu, et al., Protective conditioning for acute graft-versus-host disease. N. Engl. J. Med. 353 (2005) 1321-1331.]. Currently more than 100 transplants have been performed, and the incidence of acute GVHD has been about 4% when both MRD and MUD transplants are combined. Almost all recipients became complete chimeras after receiving grafts that contained 2-3x10(8) CD3(+) T cells/kg. In further studies, we applied the same TLI and ATG conditioning regimen to combined kidney and G-CSF "mobilized" blood stem cell transplantation from HLA-matched sibling donors. The hematopoietic grafts in the latter protocol were selected CD34(+) cells with 1x10(6) CD3(+) T cells/kg added back to the hematopoietic cells. Preliminary results indicate that stable mixed chimerism can be achieved using this protocol allowing for complete immunosuppressive drug withdrawal without GVHD or subsequent rejection episodes. Thus, conditioning with TLI based regimens can simultaneously protect against organ graft rejection and GVHD. Levels of chimerism are dependent upon the content of donor T cells in the hematopoietic graft.

    View details for DOI 10.1016/j.bcmd.2007.06.019

    View details for Web of Science ID 000252171800009

    View details for PubMedID 17827036

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