Transplantation/Haematopoietic Stem Cell

The biology of haematopoietic-stem-cell transplantation

 * Stem cells have two main properties. First, they must be able to perpetuate themselves, that is, they must be able to duplicate without modification. This process is called 'self-renewal'. In addition, under the right conditions, they must be able to differentiate into a number of different mature cell types.
 * Haematopoietic stem cells are capable of producing the various types of blood cells, including erythrocytes (red cell), platelets, lymphocytes, monocytes, granulocytes, and natural killer cells.
 * Haematopoietic-stem-cell transplantation is based on the principle that the diseased haematopoietic system of a patient can be eliminated by chemotherapy or radiation, and replaced with the haematopoietic system of another human being. In order for this procedure to be effective, the transplanted stem cells cannot be rejected by the recipient, they must engraft and behave as stem cells in the new host, that means being capable of self-renewal and differentiation. In addition, if the donor cells themselves elicit an immune response against the recipient, what is called 'graft-versus-host disease', this reaction cannot be so severe that creates an insurmountable clinical problem.
 * Haematopoietic-stem-cells reside in the bone marrow.
 * The success of haematopoietic-stem-cell transplantation therefore depends on our ability to control the immune reactions taken place between donor and recipient. These immune reactions are a function of whether cells recognise each other as self or as foreign. Although all proteins can play a role in this recognition, the role they play is minor, and they are referred to as 'minor histocompatibility antigens'—minor compared to the role played by HLA molecules. HLA molecules are the central molecules in the immune system, they are called the 'major histocompatibility comples' (MHC). MHC is the generic name for the genetic system responsible for these molecules in all vertebrates, whereas HLA is how this * system is called in humans. For this reason HLA matching between patients and donors is critical in transplantation.

The history of haematopoietic-stem-cell transplantation

 * The first clinical haematopoietic-stem-cell transplants were performed in 1968. Children with congenital immune deficiencies received bone-marrow from siblings that had identical HLA phenotypes.
 * At the beginning the diseases mostly being treated were not leukaemia, but immune deficiencies and aplastic anaemias.
 * In the early 1970s ED Thomas proved that refractory leukaemia could be effectively treated with bone-marrow transplantation. See PubMed and PubMed
 * In the 1980s most of the procedures were for the treatment of leukaemia, AML, ALL and CML. At this time most donors were related donors.
 * In the 1990s autologous haematopoietic-stem-cell transplants were proven to be a superior treatment for multiple myeloma. See PubMed
 * At the present time about 60,000 transplants are performed every year throughout the world.

1.	Improvement of the representation of genetic diversity in bone marrow donor registries
The success for a patient of finding a match depends on his ethnicity. Ethnic minorities are in a disadvantaged position. Registries must make an effort in the recruitment of donors to increase the representation of minorities.

2.	Improvement of the quality of HLA typing in bone marrow donor registries
Three reasons can be mentioned to account for the poor quality of HLA typing in donor registries. First, in so far as these registries have been built during an extended period of time, and the typing methods have been improving over time, older registry entries are of poorer quality than newer one. Second, limited resources for donor recruitment often leads to suboptimal methods in HLA typing and poor quality results. And third, registry officials must make strategic decisions under financial constraints sometimes leading to poor outcomes (e.g. failing to type for HLA-C).

3.	Formalisation of the process of matching patients to donors
The principles of histocompatibility have been applied to the selection of donors for bone marrow transplantation with remarkable imprecision. The distinction between the graft-versus-host direction on one hand, and the host-versus-graft direction on the other hand, is often ignored. Not all the HLA loci known to be relevant in histocompatibility are always taken into account. The most inexact terminology has dominated the practice of matching patients and donors. Expressions such as ‘antigen match’ or ‘allele match’ hide our lack of method. The concept of ‘high resolution typing’ leaves everybody in the dark. Endless talk about typing ambiguities is the inevitable result of deeply seated conceptual confusion. Matching is carried out on account of the given names HLA alleles have received (often without system) lacking any insight into what may be behind a name, sometimes calling a mismatch between pairs of alleles that, although have different names, for all practical purposes code exactly the same protein.

One of the puzzles of bone marrow transplantation is the different criteria used to match cord blood units and adult products, the justification for which is questionable. Outcome studies depend on clear and precise matching criteria. Obfuscation in this area is one of the reason why it has been so difficult to establish the role of HLA matching in bone marrow transplantation.

The role of KIR typing and KIR ligands, as well as that of anti-HLA antibodies is just beginning to be evaluated.

There is a need to formalise HLA matching and clarify the conceptual confusion in histocompatibility.

4.	Optimisation of the administrative efficiency of registries to reduce the time it takes to make donor products available.
The fact that lekaemia patients must first go into remission to receive a successful bone marrow transplant is often presented as an argument in favour of the view that there is plenty of time to go and look for a donor, and delay in the availability of bone marrow for transplantation is not an issue. But how many patients go back into relapse, or simply die, waiting for a transplant?

Financial clearance from insurance companies, tedious retyping of numerous donors with potential matches and imprecise original typing, failure to localize a matched donor, all delay the availability of bone marrow or peripheral haematopoietic stem cells for transplantation.

One of the benefits of cord blood units is claimed to be their ready availability.

5.	Application of knowledge about the biology of haematopoietic stem cells to optimize conditioning protocols and infusion practices.
Studies in mice show that the bone marrow has a limited capacity to host haematopoietic stem cells. Transplantation implies replacing host stem cells with donor stem cells. Radiation, for example, removes stem cells from their niche, as researchers in this area call it. There may be a competitive process in occupying these niches, if so, how donor cells are infused may affect their chances of engraftment. It has been observed that infusion in a single bolus is less effective that infusion of multiple smaller boluses over time. At this point, conditioning protocols do not take advantage of this basic biological knowledge.

6.	Extension of the use of bone marrow transplantation to leukaemia patients for whom it is not considered now indicated.
Extreme conditioning protocols have prevented older patients in the past from receiving bone marrow transplantation. New non-ablative protocols have extended the age of patients that can benefit from transplantation.

The morbidity associated with graft-versus-host disease has inhibited the more extended clinical application of bone marrow transplantation. As HLA matching becomes more efficient and the treatment of graft-versus-host disease becomes more effective, clinicians will be less reticent to the more wide use of bone marrow transplantation. Transplantation is more effective in patients with better prognosis, but paradoxically they are less likely to be transplanted out of fear of the complications of transplantation.

7.	Expansion of the use of bone marrow transplantation to other clinical conditions besides haematopoietic malignancies.
A provisional list of clinical conditions where bone marrow transplantation may play an important role in their therapy include the following conditions:
 * Non-haematopoietic malignant diseases
 * Breast cancer
 * Germ-cell tumours
 * Renal cell tumours
 * Neuroblastoma
 * Non-malignant acquired diseases
 * Aplastic anaemia
 * Paroxysmal nocturnal haemoglobinuria
 * Autoimmune diseases
 * HIV infection
 * Inherited diseases
 * Thalassaemia
 * Sickle cell disease
 * Immunodeficiency syndromes
 * Osteopetrosis
 * Storage diseases
 * Macrophage and granulocyte disorders
 * Fanconi’s anaemia

8.	Evaluation of how tolerable individual mismatches are.
Unfortunately there is a lack of systematic research in the evaluation of immune tolerance in individual mismatches. Such research is essential in the selection of donors when there is not a perfect match.

It has been only recently that knowledge of the structure of the HLA molecule has been used to ignore in clinical practice differences between alleles in areas of the molecule that are not likely to elicit an immune response. The concept of ‘antigen recognition site’ is now widely used to indicate which area of the molecule deserves our attention. Sound and solid research in the evaluation of immune tolerance in transplantation is the key to learn how to mismatch donors and recipients, to learn how to tell that one mismatch is more tolerable than another.

9.	Creation of protocols to allow the use of mismatched donors.
The limits of HLA matching must be set clearly. Some individuals have unique HLA phenotypes not shared by anybody else. Other individuals have such rare phenotypes that only by typing the entire world human population could one expect to find a match. Rather than asking ourselves what the necessary donor registry size to match an arbitrary percentage of patients with a disease curable with bone marrow transplantation is, we should be asking ourselves what size of registry is feasible to have, and then what percentage of the patient population would be covered. This would be considered the limits of HLA matching. Patients with extremely rare phenotypes cannot expect to have a fully matched bone marrow other than from an identical sibling.

Protocols must be developed to treat these patients that cannot be expected to find a match. Such protocols are currently being developed for the so-called haplo-identical transplants. It is true, as the advocates of these procedures point out, that almost everybody has a haplo-identical donor in his family, but it also true that a partially matched registry donor may be preferable than a haplo-identical sibling.

10.	Multiple transplants for multiple purposes
The biological effect of the transplantation of haematopoietic stem cell is multiple: haematopoietic reconstitution, immunologic reconstitution, graft rejection, graft-versus-host disease, graft-versus-leukaemia effect, etc. Some of these effects are beneficial and others are detrimental. Some beneficial effects go together with some detrimental effects like graft-versus-leukaemia effect and graft-versus-host disease. In so far as these effects are a function of the degree of HLA matching as well as KIR matching and HLA-antigen-antibody matching, it is possible to manipulate the effect of transplantation by enhancing the degree of matching or mismatching that induces the effect. And as long as different desirable effects require different levels of matching, it is possible to develop a strategy of performing multiple transplants on a patient to produce multiple beneficial effects in sequence.

Books

 * Applebaum FR, Forman SJ, Negrin RS, Blume KG. Thomas's Hematopoietic Cell Transplantation. 4th Ed. (John Willey & Sons 2007) amazon.com
 * Parham P. The Immune System. 3rd Ed. (Garland Science 2009) amazon.com

Allogeneic hematopoietic cell transplantation

 * Allogeneic hematopoietic cell transplantation: the state of the art. ExpertRevHematol_2010_3_285

Cord-blood transplantation

 * Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. NewEngJMed_2004_351_2265