scholarly journals Treatment with immunotoxin

2001 ◽  
Vol 356 (1409) ◽  
pp. 681-689 ◽  
Author(s):  
Stuart J. Knechtle
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Tolerance Induction ◽  
Cell Depletion ◽  
Skin Grafts ◽  
T Cell Depletion ◽  
Human Organ ◽  
Donor Bone Marrow ◽  
Islet Transplants

T–cell depletion prior to or beginning at the time of transplantation has been shown to be a valuable adjunct to the induction of immunological unresponsiveness. Both total lymphoid irradiation and anti–lymphocyte globulin have been used for this purpose in experimental models of transplantation as well as in human organ transplant recipients. However, these methods of T–cell depletion are limited in their ability to deplete T cells selectively due to non–specific targeting and limited efficacy. A new anti–CD3 immunotoxin has been developed with a far more potent ability to deplete T cells selectively as measured by flow cytometry analysis of peripheral blood T lymphocytes as well as lymph node lymphocytes. This immunotoxin is well tolerated by rhesus monkeys when administered in vivo . When administered as a single immunosuppressive agent pretransplant, it substantially promotes allograft survival, inducing tolerance in at least one–third of recipients as measured by subsequent acceptance of donor skin grafts and rejection of third–party skin grafts. When administered on the day of transplant in combination with steroid pretreatment and a brief course of deoxyspergualin or mycophenolate mofetil (4 to 14 days), long–term unresponsiveness is also produced and in a more reliable manner than using immunotoxin alone. A new immunotoxin directed at the human CD3ε has been developed with excellent potency in T–cell killing and lacking the Fc portion of the CD3 antibody. This construct may be useful for T–cell depletion in humans and has a potential application in tolerance induction in human organ transplantation. Lessons learned from anti–CD3 immunotoxin in the non–human primate model to date include (i) profound (2–3 log) depletion of T–cells can be accomplished safely without inducing lymphoma or infection, (ii) such depletion is a useful adjunct for tolerance induction to allogeneic organ transplants, and (iii) tolerance to both allogeneic renal transplants and xenogeneic islet transplants has been accomplished using such strategies to date in non–human primates and in pigs. Immunotoxin may be useful for the induction of chimerism using strategies that include donor bone marrow infusion. Successful strategies for tolerance induction have also been developed using immunotoxin without the adjunct of donor bone marrow or stem cell infusion. Clinical application of immunotoxin will use a newly engineered construct with the potential for causing cytokine release, less susceptibility to neutralization by anti–diphtheria antibody and not dependent on chemical conjugation of an antibody and toxin. The usefulness of immunotoxin is directly related to its tremendous potency for depleting T cells. Based on results in nonhuman primates, it is anticipated that it will become a useful agent in tolerance induction in humans.

scholarly journals Augmentation of donor bone marrow engraftment in histoincompatible murine recipients by granulocyte/macrophage colony-stimulating factor

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 320-328 ◽  
Author(s):  
BR Blazar ◽  
MB Widmer ◽  
CC Soderling ◽  
DL Urdal ◽  
S Gillis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Ex Vivo ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Gm Csf ◽  
Donor Bone Marrow ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract T cell depletion of donor bone marrow can prevent graft v host disease (GVHD) in human and murine marrow graft recipients. However, engraftment in the recipient may be compromised as a consequence of donor marrow T cell depletion. The effect of recombinant murine granulocyte/macrophage colony-stimulating factor (rmu GM-CSF) on engraftment and hematologic reconstitution was evaluated in a murine allogeneic bone marrow transplantation (BMT) model involving T cell depletion of marrow. Before transplantation into irradiated mice differing at major and minor histocompatibility loci, rmu GM-CSF was preincubated with T cell-depleted donor marrow. When low degrees of engraftment were noted in control recipients, treatment of donor marrow with high concentrations of rmu GM-CSF led to enhanced engraftment. Ex vivo donor graft incubation with rmu GM-CSF or a single in vivo injection of rmu GM-CSF were both effective means of promoting engraftment. When the engraftment rate in control recipients was high, rmu GM-CSF did not have an identifiable effect. Only slight increases in hematologic recovery were detected regardless of the rate of engraftment. Neither post-BMT survival nor marrow stem cell capacity was affected by rmu GM-CSF incubation. Furthermore, growth factor administration did not have a significant effect on the incidence of GVHD in recipients of non-T cell-depleted bone marrow splenocyte preparations. In vitro natural killer-mediated target cell lysis was not altered by incubation of effector cells with rmu GM-CSF. These results demonstrate the potential of ex vivo rmu GM-CSF treatment of donor marrow to facilitate engraftment across extensive histo- compatibility barriers.

scholarly journals Effects of T cell depletion in radiation bone marrow chimeras. II. Requirement for allogeneic T cells in the reconstituting bone marrow inoculum for subsequent resistance to breaking of tolerance.

1988 ◽  
Vol 168 (2) ◽  
pp. 661-673 ◽  
Author(s):  
M Sykes ◽  
M A Sheard ◽  
D H Sachs
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Failure ◽  
Recipient Strain ◽  
Cell Depletion ◽  
Mixed Chimerism ◽  
T Cell Depletion ◽  
Mixed Chimeras

The ability of normal recipient-type lymphocytes to break tolerance in long-term allogenic radiation chimeras has been investigated. Reconstitution of lethally irradiated mice with a mixture of syngeneic and allogeneic T cell-depleted (TCD) bone marrow (BM) has previously been shown to lead to mixed chimerism and permanent, specific tolerance to donor and host alloantigen (3-5). If allogeneic T cells are not depleted from the reconstituting inoculum, complete allogeneic chimerism results; however, no clinical evidence for GVHD is observed, presumably due to the protective effect provided by syngeneic TCD BM. This model has now been used to study the effects of allogenic T cells administered in reconstituting BM inocula on stability of long-term tolerance. We have attempted to break tolerance in long-term chimeras originally reconstituted with TCD or non-TCD BM by challenging them with inocula containing normal, nontolerant recipient strain lymphocytes. tolerance was broken with remarkable ease in recipients of mixed marrow inocula in which both original BM components were TCD. In contrast, tolerance in chimeras originally reconstituted with non-TCD allogeneic BM was not affected by such inocula. Susceptibility to loss of chimerism and tolerance was not related to initial levels of chimerism per se, but rather to T cell depletion of allogeneic BM, since chimeras reconstituted with TCD allogeneic BM alone (mean level of allogeneic chimerism 98%) were as susceptible as mixed chimeras to the tolerance-breaking effects of such inocula. The possible contribution of GVH reactivity to this resistance was investigated using an F1 into parent strain combination. In these animals, the use of non-TCD F1 BM inocula for reconstitution did not lead to resistance to the tolerance-breaking effects of recipient strain splenocytes. These results suggest that the ability of T cells in allogeneic BM inocula to confer resistance to late graft failure may be related to their graft-vs.-host reactivity, even in situations in which they do not cause clinical GVHD. These findings may have relevance to the mechanism whereby T cell depletion of allogeneic BM leads to an increased incidence of late graft failure in clinical BM transplantation situations.

scholarly journals Allogeneic bone marrow transplantation with a fixed low number of T cells in the marrow graft [see comments]

Blood ◽  
1994 ◽  
Vol 83 (10) ◽  
pp. 3090-3096 ◽  
Author(s):  
LF Verdonck ◽  
AW Dekker ◽  
GC de Gast ◽  
ML van Kempen ◽  
HM Lokhorst ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Morbidity And Mortality ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Standard Risk

Abstract Despite prophylaxis with immunosuppressive drugs, severe acute graft- versus-host disease (GVHD) remains a major cause of morbidity and mortality in patients transplanted with unmodified bone marrow (BM) grafts from HLA-identical siblings. Although T-cell depletion of the BM graft has evolved as the most effective method to prevent severe acute GVHD, this beneficial effect is counterbalanced by an increased rate of graft failure and relapse of the disease. To find an approach to T-cell depletion that may avoid these extreme risks, we gave BM recipients a fixed low number of 1 x 10(5) donor T cells per kilogram of recipient's body weight in the graft. This corresponds with 99% T-cell depletion and is achieved by the addition of T cells to the graft that was previously depleted of T cells. A total of 70 patients with hematologic malignancies or aplastic anemia, including 40 patients with standard- risk leukemias, received BM grafts, depleted of T cells according to this approach, from HLA-identical siblings. The preparative regimen consisted of cyclophosphamide and total body irradiation. The patients also received a short course of cyclosporine posttransplant. Graft failure did not occur. Acute GVHD, only grade I or II, was seen in 70% of the patients and was limited to the skin in all patients. Chronic GVHD occurred in 31% of the patients and, with the exception of 1 patient, was limited to the skin as well. Relapse occurred in 3 of 40 (8%) patients with standard-risk leukemias, resulting in a projected survival at 5 years of 80%. Patients with standard-risk diseases had a procedure-related mortality of 11%. Quality of life, determined 1 year after BM transplant, was good in almost all patients with standard-risk diseases. Thus, this approach of T-cell depletion may be an approach that avoids the development of severe acute and chronic GVHD without damaging the function or antileukemic effect of the graft and that has a low transplant-related morbidity and mortality.

Prevention of graft-versus-host disease in HLA-matched bone marrow transplantation for malignant diseases: a multicentric study of 62 patients using 3-pan-T monoclonal antibodies and rabbit complement.

1987 ◽  
Vol 5 (3) ◽  
pp. 426-435 ◽  
Author(s):  
E Racadot ◽  
P Hervé ◽  
F Beaujean ◽  
J P Vernant ◽  
M Flesch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Graft Failure ◽  
Conditioning Regimen ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Multicentric Study ◽  
Rabbit Complement

In order to evaluate the effectiveness and reproducibility of T cell depletion in human leukocyte antigen (HLA)-matched bone marrow graft to prevent graft-v-host disease (GVHD), our multicentric study (nine different centers) investigated 62 consecutive patients with poor prognosis leukemia or hematosarcoma from June 1984 to November 1985. The data were updated October 1, 1986, and the mean follow-up was 18 +/- 4.3 months. T cells were depleted with a combination of 3-pan-T cell monoclonal antibodies (CD2 "D66"; CD5 "A50"; CD7 "I21") with a single incubation of rabbit complement (C'). The average number of T cells infused was 0.66 X 10(6) +/- 0.56/kg body weight. Twenty-six patients received chemoprophylaxis for GVHD, 16 received methotrexate, and ten received cyclosporin A. Only a single case of severe (greater than grade II) GVHD was observed, yet the incidence of graft failure was 19%. Factors that might have influenced the occurrence of graft failure appear to be the lack of radiotherapy in the conditioning regimen; the conditioning regimen itself (fractionated total body irradiation [TBI], 12 Gy, v single dose is better than TBI, 10 Gy, but still not statistically significant); and the age of the patients (high-risk after 30 years of age). In contrast, neither the number of nucleated cells reinfused nor the level of T cell depletion (provided the T cells were below critical numbers) seemed to have an influence, nor did chemoprophylaxis for GVHD or splenectomy in chronic granulocytic leukemia (CGL) patients. The survival of graft failure patients was very poor (one of 11; survival at 15 months of the initial graft). Thus, our study demonstrates the reproducibility and high effectiveness in preventing GVHD by immunodepletion of T cells in a large-scale multicentric assay, in which compliance with the protocol of immunodepletion was reasonably good. This study thus provides interesting clues to overcoming graft rejection.

An Improved Method for T-Cell Depletion of Allogeneic Histoincompatible Donor Bone Marrow

1983 ◽  
Vol 1 (1) ◽  
pp. 79-86 ◽  
Author(s):  
H. OZER ◽  
T. HAN ◽  
A. EARLY ◽  
M. O'LEARY ◽  
D. THOMPSON ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Depletion ◽  
Improved Method ◽  
T Cell Depletion ◽  
Donor Bone Marrow
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