Biomedical subjects

Massimo F Martelli

Publications and source records attributed to Massimo F Martelli.

43 records · Page 3Linked to original sources

PubMed2002

Transplants across human leukocyte antigen barriers.

Clinical experience with full haplotype-mismatched stem cell transplants has a 20-year history. Early results in leukemia patients were disappointing because of a high incidence of severe graft-versus-host disease (GvHD) in T-replete transplants or high rejection rates in T-cell-depleted transplants. The breakthrough came with introduction of a megadose T-cell-depleted progenitor cell transplant following a high-intensity conditioning regimen and the realization that donor natural killer (NK) cell alloreactivity also plays a role in facilitating engraftment and in preventing relapse. Treating end-stage patients inevitably confounded clinical outcome in early pilot studies. Today, high-risk acute leukemia patients are treated at less advanced stages of disease, receive a reasonably well-tolerated conditioning regimen, and benefit from advances in post-transplant immunological reconstitution. These factors have markedly reduced transplant-related mortality. Overall, event-free survival (EFS) and transplant-related mortality (TRM) compare favorably with reports from unrelated matched transplants. T-cell-depleted megadose stem cell transplant from a mismatched family member, who is immediately available, can now be offered as a viable option to candidates with high-risk acute leukemias.

HLA Antigens↗

PubMedDate not supplied

Crossing the HLA barriers.

Studies in mice and humans demonstrate that transplantation of hematopoietic progenitors in numbers larger than commonly used ("megadose" transplants) overcomes major genetic barriers. In vitro studies suggest that veto cells, within the population of hematopoietic progenitors, facilitate this favorable outcome. Thus, when purified CD34+ cells were added to bulk mixed-lymphocyte reactions (MLRs), they suppressed CTLs against donor's stimulators but not against stimulators from a third party. This tolerizing activity depends on cell contact and can be blocked by the caspase inhibitor BD-FMK, suggesting that the effector host T cells are deleted by apoptosis upon interaction with the CD34+ cells. Early myeloid CD33+ cells generated by short-term ex vivo expansion of CD34+ cells also exhibit veto activity, and these cells can be grown in large numbers. Tolerance induction can be further enhanced by other veto cells. Perhaps the most potent veto cell is the CD8+ CTL. However, this cell is also associated with marked graft-versus-host disease (GVHD). GVHD can be separated from the veto activity by generating anti-third party CTLs under IL2 deprivation. Under such selective pressure, only the stimulated clones which make IL2 can survive, while anti-host clones die. In vivo studies show that such anti-third party veto CTLs can be used safely for tolerance induction without GVHD.

Animals↗

PubMedDate not supplied

Alloreactive natural killer cells in mismatched hematopoietic stem cell transplantation.

Natural killer (NK) cell-mediated, donor-vs.-recipient alloresponses occur following transplantation of human leukocyte antigen (HLA) haplotype-mismatched hematopoietic stem cells (HSCs). NK cell alloreactivity reduced the risk of relapse in acute myeloid leukemia patients while improving engraftment and protecting against graft-vs.-host disease (GvHD). NK cells are primed to kill by several activating receptors. NK killing of autologous cells is prevented because NK cells co-express inhibitory receptors (killer cell Ig-like receptors, KIR) that recognize groups of (self) MHC class I alleles. As KIRs are clonally distributed, the NK population in any individual is constituted of a repertoire with different allospecificities. NK cells in the repertoire mediate alloreactions when the allogeneic targets do not express class I alleles that block them. High resolution molecular HLA typing of recipient and donor, positive identification of donor KIR genes, and in some cases, functional assessment of donor NK clones will identify haploidentical donors who are able to mount donor-vs.-recipient NK alloreactions.

Animals↗

PubMedDate not supplied

Fourth International Workshop on Haploidentical Transplants, Naples, Italy, July 8-10, 2004.

Many patients with high-risk hematological malignancies or with incurable inborn errors do not have an HLA-matched sibling and cannot find an HLA-matched donor for an allogeneic hematopoietic stem cell transplantation (SCT). Transplantation strategies using mismatched haploidentical family donors have been an important development. Although the procedure has saved patients from certain death, it is still beset by major problems like life-threatening infections--due to profound immunodeficiency following T-cell depletion and to disease relapse. At every International Workshop on Haploidentical Transplants, new data are presented, showing how scientists are attempting to improve the outcomes of mismatched transplants while reducing the severity of complications.The fourth Workshop continues in this tradition of presenting ground-breaking research. It opened with presentations of the current results with unrelated volunteer and umbilical cord blood transplants and proceeded to a session with the results of haploidentical transplants in the world with series of patients with high-risk acute leukemia, ranging in number from well over 100 in Perugia, Italy, and 80 in Haifa, Israel, to smaller groups in Europe and the United States. The session on graft engineering presented the latest results in the search for the optimal graft. The graft-vs.-leukemia effect in the haploidentical transplant was discussed in depth. Subsequently, attention focussed on one of the major problems in haploidentical transplant, that is, the delay in immunological recovery. The Workshop closed with presentations on tolerance induction that was followed by the results of ongoing registration studies being performed by the Italian GIMEMA group and the European Bone Marrow Transplant group.

Cord Blood Stem Cell Transplantation↗

PubMedDate not supplied

Graft engineering for allogeneic haploidentical stem cell transplantation.

Haploidentical stem cell transplantation has became a clinical reality in the last 10 years as it provides the chance of transplant for about 50% of patients with hematological malignancies who do not have a matched related or unrelated donor. Proper graft preparation for this type of transplant is crucial and this paper analyses our work over the past decade in the search for the optimal graft processing procedure moving from E-rosetting and soybean agglutination, through a combination of negative or positive selection of hematopoietic stem cells to the current method of one-step positive selection. In preparing a graft for haploidentical transplant, three essential requisites must be met. It must contain (1) a megadose (>10 x 10(6) x kg recipient b.w.) of hematopoietic stem cells to overcome the HLA histocompatibility barrier; (2) very few T-lymphocytes (CD3+ cells < 3 x 10(4)/kg recipient b.w.) to prevent severe acute and chronic graft-versus-host disease (GvHD); (3) very few B-lymphocytes to prevent Epstein-Barr virus-related lymphoproliferative disorders. With current graft processing technologies based on positive selection of hematopoietic stem cells, these requirements can be met. A 70-80% hematopoietic stem cell recovery ensures the target megadose is achieved in over 70% of cases with a T-cell depletion of more than 4 logs and a B-cell depletion of over 3 logs. Progress in graft processing has ensured primary, sustained engraftment rates of over 90% and has significantly reduced the incidence of severe acute GvHD and EBV-related lymphoproliferative disorders. Modern time-saving automated graft processing devices ensure reproducibility, reliability, and biological safety, which make widespread application of the haploidentical transplant currently feasible.

Cell Separation↗

PubMedDate not supplied

Hematopoietic stem cell transplantation from alternative sources in adults with high-risk acute leukemia.

Since 75% of patients with high-risk acute leukemia do not have a human leukocyte antigen (HLA)-identical sibling, alternative sources for hematopoietic stem cell transplantation (HSCT) are matched unrelated donors (MUD), unrelated umbilical cord blood (UD-UCB) and one HLA haplotype mismatched family members (haploidentical). The chance of finding a suitable donor in the international voluntary donor registries is limited by frequency of the HLA phenotype and the time required to identify the right donor from a potential panel, to establish eligibility and to harvest the cells. In adult MUD recipients, event-free survival ranges up to 50% and refers only to patients who undergo transplant, without taking into account those who do not find a donor. Umbilical cord blood offers the advantages of easy procurement, the absence of risks to donors, the reduced risk of transmitting infections, immediate availability of cryopreserved samples and acceptance of mismatches at two of the six antigens. Although UD-UCB transplantation is a viable option for children, it is seldom considered for adults. The great divergency between body weight and the number of hematopoietic cells in a standard cord blood unit, particularly if associated with a two-antigen mismatch, increases the risk of graft failure and delays hematopoietic reconstitution. Work on full-haplotype mismatched transplants has been proceeding for over 20 years. Originally, outcome in leukemia patients was disappointing because of high incidence of severe graft-vs.-host disease in T-replete transplants and high rejection rates in T-cell-depleted transplants. The breakthrough came with the use of a megadose of T-cell-depleted progenitor cells after a high-intensity conditioning regimen. Treating end-stage patients inevitably confounded clinical outcome in the early pilot studies. Today, high-risk acute leukemia patients are treated at less advanced stages of disease, receive a reasonably well tolerated conditioning regimen, and benefit from advances in post-transplant immunological reconstitution. All these factors contribute to markedly reduce transplant-related mortality. Overall, event-free survival and transplant-related mortality compare favorably with reports from unrelated matched transplants. T-cell-depleted megadose stem cell transplant from a mismatched family member, who is immediately available, can be offered as a viable option to candidates with high-risk acute leukemias.

Acute Disease↗

PubMedDate not supplied

Natural killer cell alloreactivity for leukemia therapy.

Donor-versus-recipient natural killer (NK) cell alloreactivity derives from a mismatch between donor NK clones, carrying specific inhibitory receptors for self MHC class I molecules, and MHC class I ligands on recipient cells. When faced with mismatched allogeneic targets, these donor NK clones sense the missing expression of self HLA class I alleles and mediate alloreactions. Transplantation from NK alloreactive haploidentical donors controls acute myeloid leukemia relapse and improves engraftment without causing graft-versus-host disease.

Animals↗