Influence of donor lymphocytes on the incidence of primary graft failure after allogeneic bone marrow transplatition in a murine model

Abstract

We used a murine model to determine the impact of donor lymphocyte subsets on the incidence of primary marrow graft failure after transplantation of lymphocyte-depleted bone marrow. After lethal irradiation with 7.5 Gy, Balb/c mice received 1 x 10(5) to 4 x 10(7) GvH-nonreactive (C57 x Balb)F1 or GvH-reactive C57Bl/6 marrow cells. Pretreatment with anti-Thy-1.2, anti-CD4/CD8, anti-asialo-GM1 or L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) was employed to eliminate T lymphocytes and/or natural killer cells. Primary graft failure was defined as death with neutrophils < 0.5 x 10(9)/l. To assess long-term chimaerism, the percentage of H-2b-positive spleen cells was determined. Pretreatment with anti-Thy-1.2, anti-CD4/CD8 or Leu-Leu-OMe successfully eliminated GvHR-induced mortality. Graft failure rates gradually declined from 88% after transplantation of 1 x 10(5) cells to 0% after transplantation of 4 x 10(7) C57Bl/6 cells. The incidence of graft failure, however, was not altered by T-cell depletion, provided that the unspecific loss of marrow cells was compensated for. After transplantation of GvH-nonreactive (C57 x Balb)F1 bone marrow, neither ex-vivo treatment with anti-Thy-1.2 and anti-asialo GM1 nor addition of 1 x 10(7) donor thymocytes to the allograft significantly influenced engraftment. The data obtained in our animal model suggest that the total number of marrow cells is of critical importance for successful marrow engraftment and not the presence or absence of T cells, NK cells or GvHR.

The number of donor CD3+ cells is the most important factor for graft failure after allogeneic transplantation of CD34+ selected cells from peripheral blood from HLA-identical siblings

“…12 Graft failure is usually a fatal complication. 7,9 Multiple mechanisms have been reported to contribute to graft failure after allo-SCT, such as primary disease, 13 sex pairing between donor and recipient, 7 conditioning regimen, 14,15 number of CD34 ϩ cells infused, 16 and number of residual T cells in the graft. 17 The few studies in which factors related to graft failure have been analyzed have been performed in mice 16,17 or in the context of bone marrow transplant.…”

“…7,9 Multiple mechanisms have been reported to contribute to graft failure after allo-SCT, such as primary disease, 13 sex pairing between donor and recipient, 7 conditioning regimen, 14,15 number of CD34 ϩ cells infused, 16 and number of residual T cells in the graft. 17 The few studies in which factors related to graft failure have been analyzed have been performed in mice 16,17 or in the context of bone marrow transplant. 7,[13][14][15] No analyses have been conducted in the growing setting of allogeneic transplantation of T-cell-depleted granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPCs).…”

Successful haematopoietic stem cell transplantation from a matched unrelated donor following three graft failures from HLA-mismatched related donors

“…12 In this patient, more than 7 Â 10 6 CD34+ unseperated PBSC were collected from the same sibling donor for the second transplant. 1,2 To minimize organ toxicity, reconditioning consisted only of prednisolone and OKT3. After the third transplant with PBSC from donor 2, leucocyte counts rose to 4500/ml for 12 days, before graft failure recurred.…”

“…Many mechanisms have been reported to contribute to graft rejection (underlying disease, conditioning regimen, degree of HLA disparity, number of transplanted stem cells and residual T cells). [1][2][3] Following allogeneic BMT from an HLA-identical sibling, the incidence of graft rejection/failure is 2% and increases if donors are incompatible at one HLA locus. 4 The incidence of graft rejection/failure following HLAmatched unrelated BMT was described to be 10-30%, and is as high as 50-75% among recipients of HLA-nonidentical T cell-depleted marrow.…”

Severe acute graft-versus-host disease after T-cell depleted allogeneic stem cell graft from a second donor caused by persisting T-cells from the first donor

“…The incidence of graft rejection ranges from 2 to 30%, depending on the underlying disease, conditioning regimen, degree of HLA disparity, number of transplanted CD34+ cells and number of residual T cells. [1][2][3][4][5] The outlook remains poor for patients who undergo a second allogeneic transplant due to infectious complications. Here, we report a patient who experienced graft rejection of an allogeneic SCT from a mismatched unrelated donor and underwent second allogeneic transplantation from a haploidentical related donor.…”